Treatment of conditions through pharmacological modulation of the autonomic nervous system

ABSTRACT

Methods are provided for treating a subject for a condition caused by an abnormality in the subject&#39;s autonomic nervous system. In accordance with the subject methods, at least a portion of a subject&#39;s autonomic nervous system is pharmacologically modulated with at least one beta-blocker in a manner that is effective to treat the subject for the condition. The subject methods find use in the treatment of a variety of different conditions, where such conditions include various disease conditions. Also provided are systems and kits for use in practicing the subject methods.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) to U.S.provisional application No. ______, entitled “Treatment of ConditionsThrough Electrical or Pharmacologic Modulation of the Autonomic NervousSystem” to Yun et al., filed Oct. 8, 2003, the disclosure of which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The field of this invention is the treatment of conditions associatedwith the autonomic nervous system and more specifically the treatment ofconditions through pharmacological modulation of the autonomic nervoussystem.

BACKGROUND OF THE INVENTION

There are a variety of conditions that can affect an individual's healthand well-being. The treatment of various conditions that affect thehealth and well-being of an individual has been around for centuries. Ingeneral, the armament of treatment options available to a physician totreat such conditions has increased tremendously, especially in the lastcentury.

However, while the number of treatment options has increased, typicallysuch options are merely palliative, i.e., are designed for the relief ofsymptoms of a condition rather than actually being curative of thedisorder itself. In fact, treatment protocols effectively directed atthe underlying cause of a condition are quite rare.

As such, there continues to be an interest in the development of newprotocol options for treating conditions.

SUMMARY OF THE INVENTION

Methods are provided for treating a subject for a condition caused by anabnormality in the subject's autonomic nervous system. In accordancewith the subject methods, at least a portion of a subject's autonomicnervous system is pharmacologically modulated with at least onebeta-blocker in a manner that is effective to treat the subject for thecondition. The subject methods find use in the treatment of a variety ofdifferent conditions, where such conditions include various diseaseconditions. Also provided are systems and kits for use in practicing thesubject methods.

DETAILED DESCRIPTION OF THE INVENTION

Methods are provided for treating a subject for a condition caused by anabnormality in the subject's autonomic nervous system. In accordancewith the subject methods, at least a portion of a subject's autonomicnervous system is pharmacologically modulated with at least onebeta-blocker in a manner that is effective to treat the subject for thecondition. The subject methods find use in the treatment of a variety ofdifferent conditions, where such conditions include various diseaseconditions. Also provided are systems and kits for use in practicing thesubject methods.

Before the present invention is described, it is to be understood thatthis invention is not limited to particular embodiments described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges is also encompassed within the invention, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention.

As summarized above, the subject invention provides methods for treatinga subject for a condition caused by an abnormality in the subject'sautonomic nervous system by pharmacologically modulating at least aportion of the subject's autonomic nervous system. In further describingthe subject invention, representative embodiments of the subject methodsare described first in greater detail, followed by a review of variousrepresentative applications in which the subject methods may find use.Next, a review of systems and kits for use in the subject methods isprovided.

Methods

As noted above, the subject methods are methods for treating a subjectfor a condition caused by an autonomic nervous system abnormality. Morespecifically, the subject methods are methods for treating a subject fora condition caused by an abnormality in a subject's autonomic nervoussystem by pharmacologically modulating at least a portion of thesubject's autonomic nervous system. Embodiments includepharmacologically modulating at least a portion of the autonomic nervoussystem to inhibit activity in at least a portion of the autonomicnervous system, e.g., inhibit activity in at least a portion of thesympathetic nervous system, by administering an effective amount of atleast one beta-blocker in a manner effective to treat the subject forthe condition.

Up until now, scientists have viewed biology as a complex system ofdaunting degree. Seemingly endless new relationships between variouspathways are constantly emerging during research and seem to variouslyconfirm and refute previous assumptions. This type of bottoms-upapproach to biology has led to a perception that human biology and humandiseases are perhaps too complex to successfully comprehend with currentscientific knowledge. New data is often thought to add degrees ofcomplexity to the understanding of biology and disease. More and morefocus of modern biology is on diversity and variance of normal andabnormal biology.

The inventors of the subject invention have discovered that, in fact,many, if not all, human medical conditions, including diseases, areactually governed by a coherent set of simple rules. In otherdisciplines, it has been mathematically shown that seemingly complexpatterns can emerge from simple rules. The inventors of the subjectinvention have realized that the complex myriad of seemingly unrelatedhuman diseases are actually governed by simple unifying concepts. Theinventors of the subject invention have thus approached biology, not asbottoms up exercise of collecting and analyzing complex data sets, butrather, as a top down process of identifying simple unifying principlesthat manifest in complex downstream biology. Such upstream analysis hasenabled the inventors of the subject invention to look at science at themeta-level, and the study of science at this higher stratum has yieldedsurprising answers to the nature of human biology and disease, and thusto novel treatment options for various human conditions, includingdiseases. The inventors of the subject invention have discovered thatautonomic nervous system disturbance, or abnormalities of the autonomicnervous system, is the simple rule that governs a wide range ofconditions (including diseases) that, when viewed from a clinicalstandpoint, appear to be a complex, heterogeneous, unrelated group. Theinventors of the subject invention have discovered otherwise and haveformulated novel pharmacologic strategies to treat conditions includingdisease conditions by modulating autonomic function as the basis oftherapy.

Accordingly, embodiments of the subject invention includepharmacologically modulating at least a portion of a subject's autonomicnervous system to at least inhibit activity in a portion of theautonomic nervous system, e.g., in at least a portion of the sympatheticnervous system. In accordance with the subject invention, modulating atleast a portion of autonomic nervous system may be achieved byadministering an effective amount of at least one beta-blocker.Accordingly, the subject methods include administering an effectiveamount of least one beta-blocker to a subject to inhibit activity in atleast a portion of a subject's sympathetic nervous system to effectivelytreat the subject for a condition.

Specifically, the subject invention includes pharmacologicallymodulating at least a portion of a subject's autonomic nervous system byadministering an effective amount of at least one beta-blocker toachieve a desired parasympathetic activity/sympathetic activity ratio,i.e., a desired balance between parasympathetic activity and sympatheticactivity, e.g., a balance analogous to a parasympatheticactivity/sympathetic activity ratio observed in a healthy (i.e., asubject not experiencing an abnormality in the autonomic nervoussystem), “like” or rather analogous subject, e.g., a healthy humansubject ranging in age from about 20 years old to about 25 years old(subjects other than humans will have analogous age ranges). Forexample, if the subject being treated is a human subject, theparasympathetic activity/sympathetic activity ratio provided or desiredby the subject invention may be analogous to the parasympatheticactivity/sympathetic activity ratio observed in a healthy human rangingin age from about 20 years old to about 25 years old.

Before further describing the subject methods, the autonomic nervoussystem is reviewed to provide a proper foundation for the subjectinvention.

Review of the Autonomic Nervous System

The nervous system is divided into the somatic nervous system and theautonomic nervous system (“ANS”). In general, the somatic nervous systemcontrols organs under voluntary control (e.g., skeletal muscles) and theANS controls individual organ function and homeostasis. For the mostpart, the ANS is not subject to voluntary control. The ANS is alsocommonly referred to as the visceral or automatic system.

The ANS can be viewed as a “real-time” regulator of physiologicalfunctions which extracts features from the environment and, based onthat information, allocates an organisms' internal resources to performphysiological functions for the benefit of the organism, e.g., respondsto environment conditions in a manner that is advantageous to theorganism.

The ANS conveys sensory impulses to and from the central nervous systemto various structures of the body such as organs and blood vessels, inaddition to conveying sensory impulses through reflex arcs. For example,the ANS controls constriction and dilatation of blood vessels; heartrate; the force of contraction of the heart; contraction and relaxationof smooth muscle in various organs; lungs; stomach; colon; bladder;visual accommodation, secretions from exocrine and endocrine glands,etc. The ANS does this through a series of nerve fibers and morespecifically through efferent and afferent nerves. The ANS acts througha balance of its two components: the sympathetic nervous system andparasympathetic nervous system, which are two anatomically andfunctionally distinct systems. Both of these systems include myelinatedpreganglionic fibers which make synaptic connections with unmyelinatedpostganglionic fibers, and it is these fibers which then innervate theeffector structure. These synapses usually occur in clusters calledganglia. Most organs are innervated by fibers from both divisions of theANS, and the influence is usually opposing (e.g., the vagus nerve slowsthe heart, while the sympathetic nerves increase its rate andcontractility), although it may be parallel (e.g., as in the case of thesalivary glands). Each of these is briefly reviewed below.

The Parasympathetic System

The parasympathetic nervous system is the part of the autonomic nervoussystem controlling a variety of autonomic functions including, but notlimited to, involuntary muscular movement of blood vessels and gut andglandular secretions from eye, salivary glands, bladder, rectum andgenital organs. The vagus nerve is part of the parasympathetic system.Parasympathetic nerve fibers are contained within the last five cranialnerves and the last three spinal nerves and terminate at parasympatheticganglia near or in the organ they supply. The actions of theparasympathetic system are broadly antagonistic to those of thesympathetic system, lowering blood pressure, slowing heartbeat,stimulating the process of digestion etc. The chief neurotransmitter inthe parasympathetic system is acetylcholine.

More specifically, neurons of the parasympathetic nervous system emergefrom the brainstem as part of the Cranial nerves III, VII, IX and X(vagus nerve) and also from the sacral region of the spinal cord viaSacral nerves 2, 3 and 4. Because of these origins the parasympatheticnervous system is often referred to as the ‘craniosacral outflow’.

In the parasympathetic nervous system both pre- and postganglionicneurons are cholinergic (i.e., they utilize the neurotransmitteracetylcholine) Unlike adrenaline and noradrenaline, which the body takesaround 90 minutes to metabolize, acetylcholine is rapidly broken downafter release by the enzyme cholinesterase. As a result the effects arerelatively brief in comparison to the sympathetic nervous system.

Each preganglionic parasympathetic neuron synapses with just a fewpostganglionic neurons, which are located near—or in—the effector organ,a muscle or gland. As noted above, the primary neurotransmitter in theparasympathetic system is acetylcholine (“Ach”) such that ACh is theneurotransmitter at all the pre- and many of the postganglionic neuronsof the parasympathetic system. However, some of the postganglionicneurons release nitric oxide as their neurotransmitter.

The Sympathetic System

The sympathetic nervous system is the part of the autonomic nervoussystem comprising nerve fibers that leave the spinal cord in thethoracic and lumbar regions and supply viscera and blood vessels by wayof a chain of sympathetic ganglia running on each side of the spinalcolumn which communicate with the central nervous system via a branch toa corresponding spinal nerve. The sympathetic nervous system controls avariety of autonomic functions including, but not limited to, control ofmovement and secretions from viscera and monitoring their physiologicalstate, stimulation of the sympathetic system inducing e.g. thecontraction of gut sphincters, heart muscle and the muscle of arterywalls, and the relaxation of gut smooth muscle and the circular musclesof the iris. The chief neurotransmitter in the sympathetic system isadrenaline which is liberated in the heart, visceral muscle, glands andinternal vessels, with acetylcholine acting as a neurotransmitter atganglionic synapses and at sympathetic terminals in skin and skeletalmuscle blood vessels. The actions of the sympathetic system tend to beantagonistic to those of the parasympathetic system.

More specifically, the preganglionic motor neurons of the sympatheticsystem arise in the spinal cord. They pass into sympathetic gangliawhich are organized into two chains that run parallel to and on eitherside of the spinal cord. The neurotransmitter of the preganglionicsympathetic neurons is acetylcholine (“Ach”) which stimulates actionpotentials in the postganglionic neurons.

The neurotransmitter released by the postganglionic neurons isnonadrenaline (also called norepinephrine). The action of noradrenalineon a particular structure such as a gland or muscle is excitatory issome cases, inhibitory in others. At excitatory terminals, ATP may bereleased along with noradrenaline.

Activation of the sympathetic system may be characterized as generalbecause a single preganglionic neuron usually synapses with manypostganglionic neurons and the release of adrenaline from the adrenalmedulla into the blood ensures that all the cells of the body will beexposed to sympathetic stimulation even if no postganglionic neuronsreach them directly.

Methods of Treating a Subject for a Condition

As indicated above, the subject invention provides methods of treating asubject for a condition associated with the autonomic nervous system andmore specifically the treatment of a condition through pharmacologicalmodulation of the autonomic nervous system that includes administrationof at-least one beta-blocker. Embodiments include treating a subject fora condition caused by an abnormality in the subject's autonomic nervoussystem by pharmacologically modulating at least a portion of thesubject's autonomic nervous system to at least decrease or inhibitsympathetic activity, i.e., to increase the parasympatheticactivity/sympathetic activity ratio or increase parasympathetic activityrelative to sympathetic activity in at least a portion of the autonomicnervous system. By “pharmacologically modulating at least a portion of asubject's autonomic nervous system” is meant altering or changing atleast a portion of an autonomic nervous system by pharmacological meansto provide a change, alteration or shift in at least one component oraspect of the autonomic nervous system, as will be described in greaterdetail below. The pharmacological modulation of the autonomic nervoussystem may affect central motor output and/or nerve conduction and/ortransmitter release and/or synaptic transmission and/or receptoractivation, but in any event is a change that provides an increase inthe parasympathetic activity/sympathetic activity ratio (as used herein,“activity” and “function” are used interchangeably), at least byinhibiting or decreasing sympathetic activity.

For example, embodiments include pharmacologically modulating at least aportion of a subject's autonomic nervous system to alter, shift orchange parasympathetic activity and/or sympathetic activity from a firststate to a second state, where the second state is characterized atleast by a decrease or inhibition of at least a portion of thesympathetic nervous system relative to the first state, e.g., anincrease in the parasympathetic activity/sympathetic activity ratiorelative to the first state. Embodiments include pharmacological methodsof decreasing activity in at least one sympathetic nerve fiber toachieve a decrease in at least a portion of the sympathetic system,e.g., to increase the parasympathetic activity/sympathetic activityratio. Accordingly, embodiments include pharmacologically inhibitingactivity in at least one sympathetic nerve fiber to achieve an increasedparasympathetic activity relative to sympathetic activity. Embodimentsof the subject invention include administering an effective amount ofone or more pharmacological agents (at least one of which is abeta-blocker) to both increase activity in at least a portion of theparasympathetic system, e.g., increase activity in at least oneparasympathetic nerve fiber, and inhibit activity in at least a portionof the sympathetic nervous system, e.g., in at least one sympatheticnerve fiber, to treat a condition caused at least in part by anabnormality in the subject's autonomic nervous system.

Accordingly, a feature of embodiments of the subject methods is that theratio of parasympathetic activity to sympathetic activity is increasedby at least decreasing or inhibiting activity or function in at least aportion of the sympathetic nervous system by administration of at leastone beta-blocker. By “increased ratio of parasympathetic activity tosympathetic activity” is meant that this ratio (characterized byparasympathetic activity/sympathetic activity) is increased in at leasta portion of the autonomic nervous system, where the increase is atleast great enough to provide the desired results, e.g., great enough totreat a given condition. For example, in certain embodiments a subjectmay have an abnormal ratio of parasympathetic/sympathetic activity andthe subject invention may be employed to adjust this ratio.

While the ratio of parasympathetic function/sympathetic function may beincreased according to embodiments of the subject invention, the netresult may be a parasympathetic bias (i.e., parasympathetic dominance),sympathetic bias (i.e., sympathetic dominance) or the activities of theparasympathetic system and sympathetic system may be substantially equal(i.e., neither is dominant). By “bias” is meant that the particular“biased” component of the autonomic nervous system has a higher activitylevel than the other component. For example, a sympathetic bias refersto a higher level of sympathetic activity than parasympathetic activityat least in a portion of the autonomic nervous system, and vice versa,where such bias may be systemic or localized. Accordingly, the netresult of treating a condition by modulating at least a portion of asubject's autonomic nervous system to increase the parasympatheticactivity/sympathetic activity ratio by administering an effective amountof at least one beta-blocker may be higher or greater sympatheticactivity relative to parasympathetic activity in at least the area ofthe autonomic system targeted or rather in need of modulation, higher orgreater parasympathetic activity relative to sympathetic activity in atleast the area of the autonomic system targeted or rather in need ofmodulation, or substantially equal activity levels of sympatheticactivity and parasympathetic activity.

Accordingly, in practicing the subject methods, at least a portion of asubject's autonomic nervous system is pharmacologically modulated withan effective amount of at least one beta-blocker to increaseparasympathetic activity relative to sympathetic activity (i.e.,increase the parasympathetic activity/sympathetic activity ratio). Asnoted above, the pharmacological modulation at least provides a decreasein function or dampening of a portion of the autonomic system, e.g., mayinhibit activity in at least one sympathetic nerve fiber or inhibitnerve pulse transmission. As the subject methods includepharmacologically modulating at least a portion of a subject's autonomicnervous system, the pharmacological modulation may be systemic orregional (i.e., local). In other words, the entire autonomic nervoussystem may be modulated (e.g., the entire sympathetic nervous system maybe modulated) or only a portion may be modulated (e.g., only a portionof the sympathetic system may be modulated). For example, at least onesympathetic nerve fiber may be modulated by the administration of atleast one beta-blocker.

Accordingly, in the practice if the subject invention activity in atleast a portion of the sympathetic system may be inhibited to modulateat least a portion of the autonomic nervous system. For example,activity in any portion (or all) of the sympathetic nervous system maybe inhibited to increase parasympathetic activity relative tosympathetic activity to provide the desired ratio ofparasympathetic/sympathetic activity, e.g., activity in one or moresympathetic nerve fibers may be inhibited. By “inhibited” is meant toinclude, but is not limited to, disruption, down-regulating, dampeningand partial and complete blockage of function or nerve impulses in aparticular area of the sympathetic system.

Inhibiting or “down-regulating” activity in at least a part of thesympathetic system may be desired in a variety of instances, where suchinstances include, but are not limited, abnormal activity in at least aportion of the parasympathetic system and/or the sympathetic system. Thesubject methods may be employed, for example, in instances whereparasympathetic function is normal or abnormally low or high and/orsympathetic function is normal or abnormally low or high. The subjectmethods may be employed, for example, in instances where parasympatheticfunction is normal or abnormally high and/or sympathetic function isnormal or abnormally low or abnormally high. By “normal” is meant-thetypical autonomic nervous system functions for a healthy subject, e.g.,a healthy human subject ranging in age from about 20 years old to about25 years old. Such embodiments may be employed to alter the dominanceand/or may be employed to modulate the differential between the twosystems.

For example, prior to modulating the autonomic system according to thesubject invention, the activity in the sympathetic system may be higherthan activity in the parasympathetic system and the subject methods maybe employed to increase the parasympathetic activity to a level that isgreater than the sympathetic activity and/or may be employed to alterthe differential or difference in activity levels of the two systemssuch as decreasing the difference in activity levels or increasing thedifference in activity levels which may or may not result in sympatheticactivity that is lower than parasympathetic activity. In otherembodiments, prior to modulating the autonomic system according to thesubject invention, the activity in the parasympathetic system may behigher than activity in the sympathetic system and the subject methodsmay be employed to alter the differential or difference in activitylevels of the two systems such as increasing the difference in activitylevels which may or may not result in sympathetic activity that remainslower than parasympathetic activity.

Accordingly, the subject methods may be employed in instances where,prior to the inhibition of activity in, e.g., at least one sympatheticnerve fiber, the sympathetic activity is higher than desired, which mayor may not be a normal state. For example, sympathetic activity may behigher than the parasympathetic activity (i.e., there exists asympathetic bias) or sympathetic activity may be less than orapproximately equal to, including equal, to parasympathetic activity,but it is desired to decrease the sympathetic activity even more and thesubject methods may be employed to modulate the differential between theparasympathetic-sympathetic systems such that the result of decreasingsympathetic activity may be a sympathetic bias, parasympathetic bias ormay be an equalization of the two systems (i.e., the activities of thetwo systems are approximately equal-including equal), regardless of thestate or relative activity levels of the two systems prior to employingthe subject methods, but the difference between theparasympathetic-sympathetic systems may be modulated, e.g., increased orreduced in certain embodiments. Accordingly, embodiments of the subjectmethods may be employed to decrease sympathetic activity below that ofparasympathetic activity and/or may be employed to modulate (decrease orincrease) the differential between the two systems, but in any event isemployed to increase the ratio of parasympathetic activity tosympathetic activity. For example, decreasing activity in at least aportion of the sympathetic system may be employed where there is anormal or an abnormally low parasympathetic function and/or abnormallyhigh sympathetic function. Such may also be desired in instances where,prior to decreasing sympathetic function in, e.g., at least onesympathetic nerve fiber, parasympathetic activity is higher than thesympathetic activity, but the differential between the two needs to beincreased further. For example, such instances may occur where a subjecthas normal or above normal (i.e., abnormally high) parasympatheticfunction, but also has elevated sympathetic function (i.e., abnormallyhigh), e.g., a relative bias towards sympathetic function-may be presentor a relative bias towards parasympathetic function may be present.Other instances include normal or below normal (i.e., abnormally low)parasympathetic activity and/or normal or above normal (i.e., abnormallyhigh) sympathetic activity. The above-described examples of instanceswhere decreasing sympathetic activity may be desired is exemplary onlyand is in no way intended to limit the scope of the invention and otherinstances where decreasing sympathetic activity to treat a conditionsuch as a disease are contemplated by the subject invention and will beapparent to those of skill in the art.

As embodiments include pharmacologically modulating a subject'sautonomic nervous system to at least inhibit activity in a portion of asubject sympathetic nervous system, it is to be understood that thepharmacological modulation in accordance with the subject invention maybe performed prior to and/or at the same time and/or subsequent to anyother medical or clinical treatment regime such as, for example,administration of one or more other pharmacological agents (i.e., nonbeta-blockers), electrical modulation of at least a portion of thesubject's autonomic nervous system, e.g., as described in copending U.S.patent application Ser. No. 10/661,368, entitled “Treatment ofConditions Through Electrical Modulation of the Autonomic NervousSystem”, the disclosure of which is herein incorporated by reference,and the like. In other words, the subject methods may include otherconcomitant therapies or treatments.

According to embodiments of the subject invention, pharmacologicalmodulation is accomplished by at least administering an effective amountof at least one beta-blocker to a subject to treat the subject for acondition caused, precipitated or otherwise exacerbated, influenced oraffected by the amount or magnitude of sympathetic activity in at leasta portion of the sympathetic nervous system. In other words, activity inat least a portion of the sympathetic system is at a level that is atleast contributing to or otherwise affecting a condition such a diseasecondition in need of treatment, and as such is in need of reduction orinhibition to treat the condition.

That is, embodiments of the subject methods include administering aneffective amount, i.e., a therapeutically effective amount, of one ormore beta-blockers to a subject to modulate at least a portion of thesubject's autonomic nervous system by at least decreasing activity in atleast a portion of the sympathetic nervous system. By “effective amount”is meant a dosage sufficient to modulate at least a portion of asubject's sympathetic nervous system for a given period of time. Theeffective amount will vary with the age and physical condition of thesubject, severity of the condition being treated, the duration of thetreatment, the nature of any concurrent treatment, the pharmaceuticallyacceptable carrier used if any, and analogous factors within theknowledge and expertise of those skilled in the art.

Accordingly, embodiments of the subject invention include administeringan effective amount of at least one beta-blocker. In certainembodiments, more than one type of beta-blocker may be administered atthe same or different times to treat the same or different condition.The effective amount of a given beta-blocker may vary somewhat fromsubject to subject, and may depend upon factors such as, but not limitedto, the age and condition of the subject, the form of the beta-blocker,the route and method of delivery, etc., as noted above. Suchbeta-blocker dosages may be determined in accordance with routinepharmacological procedures known to those skilled in the art. Forexample, beta-blockers and/or adjuvants may be administered to a subjectin an amount ranging from about 0.5 milligrams to about 1200 milligramsor more in a single oral dose, one time a day or more for days, weeks,months, years, even as long as a subject's lifetime. For example,embodiment may include administering about 100 milligrams of a givenbeta-blocker two times a day over a prolonged period of time, e.g., overabout 1-3 months, e.g., about 3 months to about 3 years or more, e.g.,orally or with a medical infusion pump or-similar device designed fordelivery of a substance over a prolonged period. The frequency ofadministration of the one or more beta-blockers may vary depending,e.g., on one or more of the factors described above. For example, thefrequency of administration may range from about 1 time per day tomultiple times per day, e.g., about 2 times or more per day or asnecessary to treat or otherwise control or manage a condition. Theduration of therapy depends on the type of condition being treated andmay range from as short as about 24 hours to as long as the life of thesubject. By “adjuvants” meant a compound that, when used in combinationwith the one or more beta-blocker compounds and/or compositions,augments or otherwise alters or modifies the resultant pharmacologicaland/or physiological responses.

Depending on the particular beta-blocker(s) administered to a subject,the beta-blocker(s) may be administered to a subject using anyconvenient means capable of resulting in the desired modulation of theautonomic nervous system. Thus, the at least one beta-blocker may beincorporated into a variety of formulations for therapeuticadministration. More particularly, the beta-blockers may be formulatedinto pharmaceutical compositions by combination with appropriate,pharmaceutically acceptable carriers. By “pharmaceutically acceptablecarrier” is meant a component such as a carrier, diluent, excipient, andthe like of a composition that is compatible with the one or morebeta-blockers and other optional ingredients of the subject beta-blockercompositions in that a pharmaceutically acceptable carrier may becombined with the beta-blocker(s) without eliminating the biological ortherapeutically effective activity of the one or more beta-blockers, andis suitable for use in subjects as provided herein without undue adverseside effects (such as toxicity, irritation, allergic response, anddeath). Side effects are “undue” when their risk outweighs the benefitprovided by the pharmaceutical bet blocker(s). Non-limiting examples ofpharmaceutically acceptable components include, but are not limited to,any of the standard pharmaceutical carriers such as phosphate bufferedsaline solutions, water, emulsions such as oil/water emulsions orwater/oil emulsions, microemulsions, and various types of wettingagents. Accordingly, the beta-blockers employed in the subject methodsmay be formulated into preparations in solid, semi-solid (e.g., gel),liquid or gaseous forms, such as tablets, capsules, powders, granules,ointments, solutions, suppositories, injections, inhalants and aerosols.As such, administration of a beta-blocker may be achieved in variousways, including, but not limited to, oral, buccal (e.g. sub-lingual),rectal, topical (including both skin and mucosal surfaces, includingairway surfaces), parenteral (e.g., subcutaneous, intramuscular,intradermal, intravenous and intrathecal), intraperiactivityal,transdermal, intracheal, intravaginal, endocervical, intrathecal,intranasal, intravesicular, in or on the eye, in the ear canal, etc.,administration. In certain embodiments, one or more beta-blockers areadministered via a transdermal patch or film system such as or analogousto that described, e.g., in U.S. Pat. Nos.: 6,503,532; 5,302,395;5,262,165; 5,248,501; 5,232,702; 5,230,896; 5,227,169; 5,212,199;5,202,125; 5,173,302; 5,154,922; 5,139,786; 5,122,383; 5,023,252;4,978,532; 5,324,521; 5,306,503; 5,302,395; 5,296,230; 5,286,491;5,252,334; 5,248,501; 5,230,896; 5,227,169; 5,212,199; 5,202,125;5,173,302; 5,171,576; 5,139,786; 5,133,972; 5,122,383; 5,120,546;5,118,509; 5,077,054; 5,066,494; 5,049,387; 5,028,435; 5,023,252;5,000,956; 4,911,916; 4,898,734; 4,883,669; 4,882,377; 4,840,796;4,818,540; 4,814,173; 4,806,341; 4,789,547; 4,786,277; 4,702,732;4,690,683; 4,627,429; and 4,585,452, the disclosures of which are hereinincorporated by reference.

As noted above, embodiments may include pharmaceutical beta-blockerformulations for oral administration that may be formulated usingpharmaceutically acceptable carriers well known in the art in dosagessuitable for oral administration. Such carriers enable thepharmaceutical formulations to be formulated in unit dosage forms astablets, pills, powder, dragees, capsules, liquids, lozenges, gels,syrups, slurries, suspensions, etc., suitable for ingestion by thepatient. Pharmaceutical preparations for oral use may be obtainedthrough combination of at least one beta-blocker with a solid excipient,optionally grinding a resulting mixture, and processing the mixture ofgranules, after adding suitable additional compounds, if desired, toobtain tablets or dragee cores. Suitable solid excipients include, butare not limited to, carbohydrate or protein fillers and include, but arenot limited to sugars, including lactose, sucrose, mannitol, orsorbitol; starch from corn, wheat, rice, potato, or other plants;cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose orsodium carboxymethylcellulose; and gums including arabic and tragacanth;as well as proteins such as gelatin and collagen. If desired,disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate; with optional lubricants, such as talcor magnesium stearate; and if desired, with diluents, buffering agents,moistening agents, preservatives and flavoring agents.

Accordingly, beta-blocker formulations suitable for oral administrationin accordance with the subject invention may be present in discreteunits, such as capsules, cachets, lozenges, tablets, and the like, eachcontaining a predetermined amount of the active beta-blocker; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Suchbeta-blocker formulations may be prepared by any suitable method ofpharmacy which includes, but is not limited to, bringing intoassociation the active beta-blocker and a suitable carrier (which maycontain one or more optional ingredients as noted above). For example,beta-blocker formulations for use with the subject invention may beprepared by uniformly and intimately admixing the active beta-blocker(s)with a liquid or finely divided solid carrier, or both, and then, ifnecessary, shaping the resulting mixture. For example, a tablet may beprepared by compressing or molding a powder or granules containing theactive beta-blocker, optionally with one or more accessory ingredients.Compressed tablets may be prepared by compressing, in a suitablemachine, the beta-blocker in a free-flowing form, such as a powder orgranules optionally mixed with a binder, lubricant, inert diluent,and/or surface active/dispersing agent(s). Molded tablets may be made bymolding, in a suitable machine, the powdered beta-blocker moistened withan inert liquid binder.

The beta-blockers of this invention may also be administered in the formof suppositories for rectal administration of the drug. Theseformulations may be prepared by mixing a beta-blocker with a suitablenon-irritating vehicle or excipient which is solid at ordinarytemperatures but liquid at the rectal temperatures and will thereforemelt in the rectum to release the drug. Such materials include, but arenot limited to, cocoa butter, carbowaxes and polyethylene glycols.Embodiments include one or more beta-blocker agent(s) made intosuppositories by mixing with a variety of bases such as emulsifyingbases or water-soluble bases.

The beta-blockers of this invention may also be administered by inintranasal, intraocular, intravaginal, and intrarectal routes includingsuppositories, insufflation, powders and aerosol formulations (forexamples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol.35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111,1995).

For example, embodiments may also include at least one beta-blocker inan aerosolized, atomized or nebulized vapor form, e.g., administrablevia a metered dose device or nebulizer, and the like such thatembodiments also include aerosolizing, vaporing or nebulizing one ormore beta-blockers for administration to a subject. Accordingly, the oneor more beta-blocker agents may be utilized in aerosol formulation or ananalogous formulation to be administered via inhalation or analogousmeans. The one or more beta-blockers employed in the practice of thepresent invention may be formulated into pressurized acceptablepropellants such as dichlorodifluoromethane, propane, nitrogen and thelike.

The beta-blockers of the invention may be delivered transdermally, by atopical route, formulated as applicator sticks, solutions, suspensions,emulsions, gels, creams, ointments, pastes, jellies, paints, powders,and aerosols. For example, embodiments may include a beta-blockerformulation in the form of a discrete patch or film or plaster or thelike adapted to remain in intimate contact with the epidermis of therecipient for a period of time. For example, such transdermal patchesmay include a base or matrix layer, e.g., polymeric layer, in which oneor more beta-blocker(s) are retained. The base or matrix layer may beoperatively associated with a support or backing. Beta-blockerformulations suitable for transdermal administration may also bedelivered by iontophoresis and may take the form of an optionallybuffered aqueous solution of the beta-blocker compound. Suitableformulations may include citrate or bis/tris buffer (pH 6) orethanol/water and contain a suitable amount of active ingredient.

The beta-blockers of the invention may also be delivered as microspheresfor slow release in the body. For example, microspheres may beadministered via intradermal injection of drug-containing microspheres,which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym.Ed. 7:623-645, 1995); as biodegradable and injectable gel formulations(see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres fororal administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). Both transdermal and intradermal routes afford constant deliveryfor weeks or months.

The beta-blocker pharmaceutical formulations of the invention may beprovided as a salt and may be formed with many acids, including but notlimited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic,succinic, etc. Salts tend to be more soluble in aqueous or otherprotonic solvents that are the corresponding free base forms. In othercases, a preparation may be a lyophilized powder that is combined withbuffer prior to use.

The beta-blocker formulations of the invention may be useful forparenteral administration, such as intravenous (IV) administration. Theformulations for administration may include a solution of thebeta-blocker dissolved in a pharmaceutically acceptable carrier. Amongthe acceptable vehicles and solvents that may be employed, include, butare not limited to, water and Ringer's solution, an isotonic sodiumchloride, etc. In addition, sterile fixed oils may conventionally beemployed as a solvent or suspending medium. For this purpose any blandfixed oil may be employed including synthetic mono- or diglycerides. Inaddition, fatty acids such as oleic acid can likewise be used in thepreparation of injectables. Accordingly, the beta-blocker agent(s) maybe formulated into preparations for injection by dissolving, suspendingor emulsifying them in an aqueous or nonaqueous solvent, such asvegetable or other similar oils, synthetic aliphatic acid glycerides,esters of higher aliphatic acids or propylene glycol; and if desired,with conventional additives such as solubilizers, isotonic agents,suspending agents, emulsifying agents, stabilizers and preservatives.These solutions are sterile and generally free of undesirable matter.These formulations may be sterilized by conventional, well knownsterilization techniques. The formulations may contain pharmaceuticallyacceptable auxiliary substances as required to approximate physiologicalconditions such as pH adjusting and buffering agents, toxicity adjustingagents, e.g., sodium acetate, sodium chloride, potassium chloride,calcium chloride, sodium lactate and the like. The concentration ofbeta-blockers in these formulations may vary widely, and will beselected based on fluid volumes, viscosities, body weight, and the like,in accordance with the particular mode of administration selected andthe patient's needs. For IV administration, the formulation may be asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agentsand-suspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol, and the like. Accordingly, beta-blocker formulationssuitable for parenteral administration may include sterile aqueous andnon-aqueous injection solutions of one or more active beta-blockeragents, which preparations may be isotonic with the blood of theintended recipient. These preparations may contain, buffers and soluteswhich render the formulation isotonic with the blood of the intendedrecipient. Aqueous and non-aqueous sterile suspensions may includesuspending agents and thickening agents. The formulations may bepresented in single- or multi-dose containers, for example sealedampoules and vials, and may be stored in a freeze-dried (lyophilized)condition requiring only the addition of the sterile liquid carrier, forexample, saline or water-for-injection immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the kind described above.

In another embodiment, the beta-blocker formulations of the inventionmay be delivered by the use of liposomes which fuse with the cellularmembrane or are endocytosed, i.e., by employing ligands attached to theliposome, or attached directly to the oligonucleotide, that bind tosurface membrane protein receptors of the cell resulting in endocytosis.By using liposomes, particularly where the liposome surface carriesligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thebeta-blocker into the target cells in vivo. (See, e.g., Al-Muhammed, J.Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol.6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).Accordingly, embodiments may include one or more beta-blockersadministered as liposomal formulations of the beta-blockers. Methods forpreparing liposomal suspensions are known in the art and thus will notbe described herein in great detail. Briefly, in those embodiments wherethe beta-blocker is an aqueous-soluble beta-blocker, the beta-blockermay be incorporated into lipid vesicles using conventional liposometechnology. In such instances, due to the water solubility of thebeta-blocker, the beta-blocker may be substantially entrained within thehydrophilic center or core of the liposomes. The lipid layer employedmay be of any conventional composition and may either containcholesterol or may be cholesterol-free. When the beta-blocker ofinterest is water-insoluble, the beta-blocker may be substantiallyentrained within the hydrophobic lipid bilayer which forms the structureof the liposome employing conventional liposome formation technology. Ineither instance, the liposomes which may be produced may be reduced insize, as through the use of standard sonication and homogenizationtechniques. Embodiments of liposomal formulations containing thebeta-blocker of interest may be lyophilized to produce a lyophilizatewhich may be reconstituted with a pharmaceutically acceptable carrier,such as water, to regenerate a liposomal suspension.

As is described in greater detail below, a pharmaceutical composition ofthe subject invention may optionally contain, in addition to abeta-blocker, at least one other therapeutic agent useful in thetreatment of a condition. Such other compounds may be of any class ofdrug-or pharmaceutical agent, including but not limited to antibiotics,anti-parasitic agents, antifungal agents, anti-viral agents, anti-tumoragents, anti-neurodegenerative agents and anti-psychotic agents. Whenadministered with anti-parasitic, anti-bacterial, anti-fungal,anti-tumor, anti-viral agents, anti-neurodegenerative, andanti-psychotic agents and the like, beta-blockers may be administered byany method and route of administration suitable to the treatment of thecondition, typically as pharmaceutical compositions.

Embodiments of the one or more beta-blockers employed in the practice ofthe subject invention may include pharmaceutical beta-blockercompositions that may be prepared from water-insoluble compounds, orsalts thereof, such as aqueous base emulsions. In such embodiments, thebeta-blocker composition will typically contain a sufficient amount ofpharmaceutically acceptable emulsifying agent to emulsify the desiredamount of the beta-blocker. Useful emulsifying agents include, but arenot limited to, phosphatidyl cholines, lecithin, and the like.

As noted above, in addition to active beta-blocker agents, thepharmaceutical beta-blocker compositions may contain other additives,such as pH-adjusting additives. In particular, useful pH-adjustingagents include acids, such as hydrochloric acid, bases or buffers, suchas sodium lactate, sodium acetate, sodium phosphate, sodium citrate,sodium borate, or sodium gluconate. Furthermore, beta-blockercompositions may, though not always, contain microbial preservatives.Microbial preservatives that may be employed include, but are notlimited to, methylparaben, propylparaben, and benzyl alcohol. Themicrobial preservative may be employed when the beta-blocker formulationis placed in a vial designed for multidose use. Pharmaceuticalbeta-blocker compositions for use in practicing the subject methods maybe lyophilized using techniques well known in the art.

The pharmaceutically acceptable excipients, such as vehicles, adjuvants,carriers or diluents, are readily available to the public. Moreover,pharmaceutically acceptable auxiliary substances, such as pH adjustingand buffering agents, tonicity adjusting agents, stabilizers, wettingagents and the like, are readily available to the public.

Embodiments may also include administration of at least one beta-blockerusing a pharmacological delivery device such as, but not limited to,pumps (implantable or external devices), epidural injectors, syringes orother injection apparatus, catheter and/or reservoir operativelyassociated with a catheter, etc. For example, in certain embodiments adelivery device employed to deliver at least one beta-blocker to asubject may be a pump, syringe, catheter or reservoir operablyassociated with a connecting device such as a catheter, tubing, or thelike. Containers suitable for delivery of at least one beta-blocker to abeta-blocker administration device include instruments of containmentthat may be used to deliver, place, attach, and/or insert the at leastone beta-blocker into the delivery device for administration of thebeta-blocker to a subject and include, but are not limited to, vials,ampules, tubes, capsules, bottles, syringes and bags.

In certain embodiments, the pharmaceutically acceptable carrier ispreservative free. By “preservative free” is meant the substantialabsence of chemical, antibacterial, antimicrobial, or antioxidativeadditives, or the like, from the pharmaceutically acceptable carriers ofthe present invention. “Substantial absence” may mean that nopreservative is present in the compositions or that trace amounts may bepresent that impart no detectable effect otherwise attributable to apreservative. For example, the pharmaceutically acceptable carrier maybe characterized by the substantial absence of chemical, antibacterial,antimicrobial, or antioxidative additives or the like (e.g., containless than about 5.0, 4.0, 3.0, 2.0, 1.0, 0.5, 0.1, 0.05, 0.01, or evenabout 0.00 percent by weight of a preservative). Further, suchformulations may be substantially or essentially free of alcohols suchas ethanol (e.g., contain less than about 5.0, 4.0, 3.0, 2.0, 1.0, 0.5,0.1, 0.05, 0.01, or even about 0.00 percent by weight of alcohols suchas ethanol). Examples of suitable beta-blocker formulations include, butare not limited to, formulations that include one or more activebeta-blocker agents and physiological saline solution (optionallyincluding other typical ingredients such as other active agents andbuffers).

As noted above, in pharmaceutical dosage forms, the agents may beadministered alone or with or in appropriate association, as well as incombination, with other pharmaceutically active compounds. As usedherein, “administered with” means that at least one beta-blocker and atleast one other adjuvant (including one or more other beta-blockers) areadministered at times sufficiently close that the results observed areindistinguishable from those achieved when at least one beta-blocker andat least one other adjuvant are administered at the same point in time.The at least one beta-blocker and at least one other adjuvant may beadministered simultaneously (i.e., concurrently) or sequentially.Simultaneous administration may be carried out by mixing the at leastone beta-blocker and at least one other adjuvant prior toadministration, or by administering the at least one beta-blocker and atleast one other adjuvant at the same point in time. Such administrationmay be at different anatomic sites or using different routes ofadministration. The phrases “concurrent administration,” “administrationin combination,” “simultaneous administration” or “administeredsimultaneously” may also be used interchangeably and mean that the atleast one beta-blocker and at least one other adjuvant are administeredat the same point in time or immediately following one another. In thelatter case, the at least one beta-blocker and at least one otheradjuvant are administered at times sufficiently close that the resultsproduced are synergistic and/or are indistinguishable from thoseachieved when the at least one beta-blocker and at least one otheradjuvant are administered at the same point in time. Alternatively, abeta-blocker may be administered separately from the administration ofan adjuvant, which may result in a synergistic effect or a separateeffect. The methods and excipients described herein are merely exemplaryand are in no way limiting.

Unit dosage forms for oral or rectal administration such as syrups,elixirs, and suspensions may be provided wherein each dosage unit, forexample, teaspoonful, tablespoonful, tablet or suppository, contains apredetermined amount of a pharmacological agent. Similarly, unit dosageforms for injection or intravenous or other suitable administrationroute may include the pharmacological agent(s) in a composition as asolution in sterile water, normal saline or another pharmaceuticallyacceptable carrier.

The term “unit dosage form,” as used herein, refers to physicallydiscrete units suitable as unitary dosages for human and animalsubjects, each unit containing a predetermined quantity ofpharmacological agent(s) of the present invention calculated in anamount sufficient to produce the desired effect in association with apharmaceutically acceptable diluent, carrier or vehicle. Thespecifications for the unit dosage forms of beta-blockers of the presentinvention depend on, for example, the particular beta-blocker(s)employed and the effect to be achieved, the pharmacodynamics associatedwith the particular beta-blocker(s) in the subject, etc.

As noted above, those of skill in the art will readily appreciate thatdose levels may vary as a function of the specific pharmacologicalbeta-blocker agent(s), the nature of the delivery vehicle, and the like.Dosages for a given pharmacological beta-blocker agent(s) are readilydeterminable by those of skill in the art by a variety of means.Exemplary dosage levels are provided herein are not to be construed tolimit the scope of the invention in any manner.

Introduction of an effective amount of at least one beta-blocker agentto a subject as described above results in a modulation of at least aportion of the autonomic nervous system, where the modulation may betemporary or permanent. More specifically, administration of aneffective amount of at least one beta-blocker agent to a subject atleast results in a temporary or permanent decrease, reduction orinhibition in activity of at least a portion of the sympathetic nervoussystem.

A wide variety of different beta-blockers may be employed in thepractice of the subject methods, where the particular beta-blocker orcombination of beta-blockers employed will depend on, e.g., the subjectbeing treated, the condition being treated, duration of treatment, etc.Representative beta-blockers include, but are not limited to, atenolol(e.g., as sold under the brand names TENORMIN), betaxolol (e.g., as soldunder the brand name KERLONE), bisoprolol (e.g., as sold under the brandname ZEBETA), carvedilol (e.g., as sold under the brand name COREG),esmolol (e.g., as sold under the brand name BREVIBLOC), labetalol (e.g.,as sold under the brand name NORMODYNE), metoprolol (e.g., as sold underthe brand name LOPRESSOR), nadolol (e.g., as sold under the brand nameCORGARD), pindolol (e.g., as sold under the brand name VISKEN),propranolol (e.g., as sold under the brand name INDERAL), sotalol (e.g.,as sold under the brand name BETAPACE), timolol (e.g., as sold under thebrand name BLOCADREN), carvedilol, and the like, and combinationsthereof.

As noted above, embodiments include administering an effective amount ofat least one beta-blocker and an effective amount of at least onenon-beta-blocker, e.g., concurrently administered. A wide variety ofdifferent non-beta-blocker pharmacological agents may be employed in thepractice of the subject methods, in addition to the administration of atleast one beta-blocker, where the particular additional pharmacologicalagent(s) employed may be, but are not limited to, analgesics (e.g.,acetaminophen (e.g., available under the brand name TYLENOL),non-steroidal anti-inflammatory drugs such as naproxen (e.g., availableunder the brand name ALLEVE), ibuprofen (e.g., available under the brandnames ADVIL, MOTRIN), and the like), antiinflammatories, etc., where incertain embodiments the non-beta-blocker agent(s) may assist inmodulating the autonomic nervous system to treat the condition ofinterest. For example, embodiments may include administering abeta-blocker and at least one non-beta-blocker agent to provide anenhanced therapeutic effect. By “enhanced therapeutic effect” is meantthat at least the initial relief of the particular condition beingtreated by the particular beta-blocker employed occurs more quickly witha combination of the beta-blocker and at least one other pharmacologicalagent such as at least one other non-beta-blocker pharmacological agent,as compared to the same doses of each component given alone; or thatdoses of one or all component(s) (the beta-blocker and at least oneother pharmacological agent such as at least one other non-beta-blockerpharmacological agent) are below what would otherwise be a minimumeffective dose (a “sub-MED”).

Accordingly, the subject invention includes treating a subject for acondition by modulating at least a portion of the subject's autonomicnervous system by administering at least one beta-blocker together withat least one other pharmacological agent such together with as at leastone other non-beta-blocker pharmacological agent. The at least onebeta-blocker and at least one non-beta-blocker agent may beconcomitantly administered as described above, i.e., they may be givenin close enough temporal proximity to allow their individual therapeuticeffects to overlap. For example, embodiments of the subject inventioninclude the co-timely administration of a beta-blocker and anon-beta-blocker. By “co-timely” with respect to drug administration ismeant administration of a second pharmacological agent (e.g., anon-beta-blocker agent) for the treatment of a condition while a firstpharmacological agent (e.g., a beta-blocker) is still present in atherapeutically effective amount. It is to be understood that in someinstances this will require sequential administration. Alternatively,multiple routes of administration may be employed, e.g., intravenous orsubcutaneous injection of a beta-blocker may be combined with oraladministration of a non-beta-blocker agent.

Embodiments also include pharmaceutical compositions in unit dosageforms that are useful in treating conditions by modulating at least aportion of a subject's autonomic nervous system and which contain abeta-blocker agent and a non-beta-blocker agent. In other words, asingle drug administration entity may include two or morepharmacological agents, e.g., a single drug administration entity mayinclude at least one beta-blocker and at least one non-beta-blocker. Forexample, a single tablet, capsule, dragee, trocheem suppository,syringe, and the like, combining two or more pharmacological agents,e.g., a single drug administration entity may include at least onebeta-blocker and at least one non-beta-blocker, would be a unit dosageform. The therapeutic agents present in a unit dosage form are typicallypresent in amounts such that, upon administration of one or more unitdoses of the composition, a subject experiences a longer lastingefficacy than with the administration of either agent alone. Suchcompositions may be included as part of a therapeutic package in whichone or more unit doses are placed in a finished pharmaceuticalcontainer. Labeling may be included to provide directions for using thecomposition in the treatment of a condition by modulating at least aportion of a subject's autonomic nervous system. The actual amounts ofeach agent in such beta-blocker/non-beta-blocker compositions will varyaccording to the specific compositions being utilized, the particularcompositions formulated, the mode of application, the particular routeof administration, and the like. Dosages for a given subject can bedetermined using conventional considerations, e.g., by customarycomparison of the differential activities of the subject compositionsand of a known agent, or by means of an appropriate, conventionalpharmacological protocol. A person of ordinary skill in the art will beable without undue experimentation, having regard to that skill and thisdisclosure, to determine a therapeutically effective amount of aparticular non-beta-blocker agent for practice of this invention. Forexample, embodiments may include dosages conventionally administered forthe particular non-beta-blocker employed, where such dosages are knownin the art.

The particular non-beta-blocker agent(s) employed will depend on thesubject being treated, the condition being treated, the at least onebeta-blocker employed, whether it is desired to increase activity in theparasympathetic system and/or decrease activity in the sympatheticsystem, etc. Exemplary, representative non beta-blocker pharmacologicalagents that may be employed in the practice of the subject inventioninclude, but are not limited to: aldosterone antagonists (e.g.,spironolactone, eplerenone, and the like); angiotensin II receptorblockades (e.g., candeartan (e.g., available under the brand nameALTACAND), eprosarten mesylate (e.g., available under the brand nameTEVETAN), irbesartan (e.g., available under the brand name AVAPRO),losartan (e.g., available under the brand name COZAAR), etelmisartin(e.g., available under the brand name MICARDIS), valsartan (e.g.,available under the brand name DIOVAN), and the like); angiotensinconverting enzyme inhibitors (e.g., benazapril (e.g., available underthe brand name LOTENSIN), captopril (e.g., available under the brandname CAPOTEN) enalapril (e.g., available under the brand name VASOTEC)fosinopril (e.g., available under the brand name MONOPRIL) lisinopril(e.g., available under the brand name PRINIVIL) moexipril (e.g.,available under the brand name UNIVASC) quinapril (e.g., available underthe brand name ACCUPRIL) ramipril (e.g., available under the brand nameALTACE) trandolapril (e.g., available under the brand name MAVIK), andthe like); statins (e.g., atorvastatin (e.g., available under the brandname LIPITOR), cerivastatin (e.g., available under the brand nameBAYCOL), fluvastatin (e.g., available under the brand name LLESCOL),lovastatin (e.g., available under the brand name MEVACOR), prevastatin(e.g., available under the brand name PRAVACHOL), simvastatin (e.g.,available under the brand name ZOCOR), and the like); triglycerideslowering drugs (e.g., fenofibrate (e.g., available under the brand nameTRICOR), genfibrozil (e.g., available under the brand name LOPID), andthe like); niacin; anti-diabetes agents (e.g., acarbose (e.g., availableunder the brand name PRECOSE), glimepiride(e.g., available under thebrand name AMARYL), glyburide (e.g., available under the brand namesMICRONASE, DIABETA), metfornin (e.g., available under the brand nameGLUCOPHASGE), miglitol (e.g., available under the brand name GLYCET),pioglitazone (e.g., available under the brand name ACTOS), repaglinide(e.g., available under the brand name PRANDIN), rosiglitazone (e.g.,available under the brand name AVANDIA), and the like); immunomodulators(e.g., interferon beta-1B (e.g., available under the brand nameBETASERON), interferon alfa-2A (e.g., available under the brand nameROFERON-A) interferon alfa-2B (e.g., available under the brand nameINTRON-A), interferon alfa-2Band Ribavirin combo pack (e.g., availableunder the brand name REBETRON), interferon alfa-N3 (e.g., availableunder the brand name ALFERON N), interferon beta-1A (e.g., availableunder the brand name AVONEX), interferon gamma immunoregulatoryantibodies that bind to or react with one of the following antigens:CD4, gp39, B7, CD19, CD20, CD22, CD401, CD40, CD40L and CD23, rituximab(e.g., available under the brand name RITUXAN), any chemical orradiopharmaceutical linked or conjugated antibodies that bind to orreact with one of the following antigens: CD4, gp39, B7, CD19, CD20,CD22, CD401, CD40, CD40L and CD23), and the like); nicotine;sympathomimetics (e.g., trimethaphan, clondine, reserpine, guanethidine,and the like); antihistamines (e.g., available under the brand nameBENADRYL, diphenhydramine, available under the brand name ACTIFED, andthe like); cholinergics (e.g., bethanechol, oxotremorine, methacoline,cevimeline, and the like); acetylcholinesterase inhibitors (e.g.,edrophonium, neostigmine, donepezil, tacrine, echothiophate,diisopropylfluorophosphate, demecarium, pralidoxime, galanthamine,tetraethyl pyrophosphate, parathoin, malathion, isoflurophate,metrifonate, physostigmine, rivastigmine, abenonium acetylchol, carbarylacetylchol, propoxur acetylchol, aldicarb acetylchol, and the like);magnesium and magnesium sulfates; calcium channel blockers (e.g.,amlodipine besylate (e.g., available under the brand name NORVASC),diltiazem hydrochloride (e.g., available under the brand names CARDIZEMCD, CARDIZEM SR, DILACOR XR, TIAZAC), felodipine plendil isradipine(e.g., available under the brand names DYNACIRC, DYNACIRC CR),nicardipine (e.g., available under the brand name CARDENE SR),nifedipine (e.g., available under the brand names ADALAT CC, PROCARDIAXL), nisoldipine (e.g., available under the brand name SULAR), verapamilhydrochloride (e.g., available under the brand names CALAN SR, COVERAHS, ISOPTIN SR, VERELAN) and the like); muscarinics (e.g., muscarine,pilocarpine, and the like); sodium channel blockers, (e.g., moricizine,propafenone, encainide, flecainide, tocainide, mexiletine, phenytoin,lidocaine, disopyramide, quinidine, procainamide, and the like);glucocorticoid receptor blockers (e.g., mifepristone, and the like);peripheral andrenergic inhibitors (e.g., guanadrel (e.g., availableunder the brand name HYLOREL), guanethidine monosulfate (e.g., availableunder the brand name ISMELIN), reserpine (e.g., available under thebrand names SERPASIL, MECAMYLAMINE, HEXEMETHONIUM), and the like); bloodvessel dilators (e.g., hydralazine hydrocholoride (e.g., available underthe brand name APRESOLINE), minoxidil (e.g., e.g., available under thebrand name LONITEN), and the like); central agonists (e.g., alphamethyldopa (e.g., available under the brand name ALDOMET), clonidinehydrochloride (e.g., available under the brand name CATAPRES), guanabenzacetate (e.g., available under the brand name WYTENSIN), guanfacinehydrochloride (e.g., available under the brand name TENEX), and thelike; combined alpha and beta-blockers (e.g., carvedilol (e.g.,available under the brand name COREG), labetolol hydrochloride (e.g.,available under the brand names NORMODYNE, TRANDATE), and the like);alpha blockers (e.g., doxazosin mesylate (e.g., available under thebrand name CARDURA), prazosin hydrochloride (e.g., available under thebrand name MINIPRESS), terazosin hydrochloride (e.g., available underthe brand name HYTRIN), and the like); combination diuretics (e.g.,amiloride hydrochloride+hydrochlorothiazide (e.g., available under thebrand name MODURETIC), spironolactone+hydrochlorothiazide (e.g.,Aldactazide), triamterene+hydrochlorothiazide (e.g., available under thebrand names DYAZIDE, MAXZIDE) and the like); potassium sparing diuretics(e.g., amiloride hydrochloride (e.g., available under the brand nameMIDAMAR), spironolactone (e.g., available under the brand nameALDACTONE), triamterene (e.g., available under the brand name DYRENIUM),and the like); nitrates (e.g., L-arginine, (e.g., available under thebrand names NITROGLYCERIN DEPONIT, MINITRAN, NITROPAR, NITROCINE,NITRODERM, NITRO DISC, NITRO-DUR, NITROGARD, NITROGLYCERIN,NITROGLYCERIN T/R, NITRO-TIME, NITROL OINTMENT, NITROLINGUAL SPRAY,NITRONG, NITRO-BID, NITROPRESS, NITROPREX, NITRO S.A., NITROSPAN,NITROSTAT, NITRO-TRANS SYSTEM, NITRO-TRANSDERMAL, NITRO-TIME,TRANSDERM-NITRO, TRIDIL. PENTAERYTHRITOL TETRANITRATE PERITRATE,PERITRATE S.A. ERYTHRITYL TETRANITRATE CARDILATE ISOSORBIDEDINITRATE/PHENOBARBITAL ISORDIL W/PB ISOSORBIDE MONONITRATE IMDUR, ISMO,ISOSORBIDE MONONITRATE, MONOKET ISOSORBIDE NITRATE DILATRATE-SR,ISO-BID, ISORDIL, ISORDIL TEMBIDS, ISORDIL DINITRATE, ISORDIL DINITRATELA, SORBITRATE, SORBITRATE SA), and the like); cyclic nucleotidemonophosphodiesterase (“PDE”) inhibitors (e.g., vardenafil (e.g.,available under the brand name LEVITRA), sildenafil (e.g., availableunder the brand name VIAGRA) tadalafil (e.g., available under the brandname CIALIS) and the like); alcohols; catecholamines inhibitors;neurotoxins, (e.g., botox and capsaicin (e.g., delivered locally, todisable sympathetic function) and the like); vasopressin inhibitors(e.g., atosiban, and the like); oxytocin inhibitors; relaxin hormone;renin inhibitors (e.g., Aliskiren, and the like); estrogen and analogues(e.g., estradiols, and the like) and metabolites; progesteroneinhibitors; testosterone inhibitors; gonadotropin-releasing hormoneanalogues (GnRH-As); gonadotropin-releasing hormone inhibitors (e.g.,Leuprolide Acetate, and the like); vesicular monoamine transport (VMAT)inhibitors (e.g., tetrabenazine, and the like); dipeptidyl peptidase(DP) IV inhibitors (DP4 inhibitors) (e.g., LAF237, P93/01, P32/98,valine pyrrolidide, and the like); melatonin; and combinations thereof.

Accordingly, in practicing the subject methods, an effective amount ofat least one beta-blocker is administered to a subject to treat acondition affecting the subject. As noted above, the particular dosage,mode of administration, treatment times, etc., will vary according to avariety of factors, but will generally fall within the ranges providedabove.

For example, embodiments include modulating sympathetic activity byadministration of an effective amount of atenolol. Such embodiments mayinclude administering a beta-blocker such as atenolol orally, e.g., inthe form of an extended-release capsule or tablet. In those embodimentsthat include administering an effective amount of a beta-blocker, e.g.,atenolol, orally by extended-release capsule or tablet, typically,though not always, the capsule or tablet is administered whole, i.e.,not crushed, broken or chewed before swallowing. In those embodimentsthat include administering an effective amount of a beta-blocker such aspropranolol orally by oral solution of propranolol, the oral solution isadministered by mouth and may be taken or mixed with a liquid such aswater, juice, carbonated rink, etc. or other food or drink product suchas applesauce, pudding, etc.

As noted above, the dose of beta-blocker will be different for differentsubject, conditions treated, etc. The following embodiments describeaverage doses and may vary. Such are for exemplary purposes only and arein no way intended to limit the scope of the invention. For example, thenumber of capsules or tablets, teaspoonfuls of solution, and the like,administered depends at least in part on the strength of the particularbeta-blocker administered. Furthermore, the number of doses administeredeach day, the time allowed between doses, and the length of time asubject takes the medicine, etc., depend on the condition being treated,i.e., the condition for which a subject is taking the beta-blocker.

As noted above, embodiments may include administering an effectiveamount of acebutolol to treat a condition. Such embodiments may includeadministering oral dosage forms (capsules and tablets) of acebutololranging from about 200 milligrams (mgs.) to about 1200 mgs., e.g., fromabout 200 mgs. to about 800 mgs. Such oral dosages may be administeredas a single dose one time a day, two times a day, or divided into twodaily doses for an adult, etc.

Embodiments may include administering atenolol to treat a condition.Such embodiments may include administering adult oral dosage forms(e.g., tablets) of atenolol (e.g., available under the brand nameTENORMIN) that range from about 25 mgs. to about 100 mgs. once a day.For example, administration may include about 50 mgs. once a day, orabout 100 mgs. of atenolol once a day, or about 50 mgs. atenolol twotimes a day, e.g., for about six to about nine days. Embodimentsthat-include administering atenolol in adult injection dosage forms mayinclude about 5 mgs. given over 5 minutes, repeated ten minutes later.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of betaxolol to treat a condition. Such embodiments may includeadministering about 10 mgs. of betaxolol as an adult dosage form once aday.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of bisoprolol (e.g., available under the brand name ZEBETA) totreat a condition. Such embodiments may include administering about 5mgs. to about 10 mgs. of bisoprolol as an adult oral dosage forms (e.g.,tablets) once a day.

Embodiments may include administering adult-oral dosage forms (e.g.,tablets) of carteolol to treat a condition. Adult oral dosage forms(e.g., tablets) of carteolol may include about 0.5 mgs. to about 10 mgs.once a day.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of labetalol to treat a condition. Adult oral dosage forms(e.g., tablets) of labetalol may include about 100 mgs. to about 400mgs. two times a day. Adult injection dosage forms may include about 20mgs., e.g., injected slowly over about two minutes with additionalinjections of about 40 mgs. and about 80 mgs. given about every tenminutes if needed, up to a total of about 300 mgs., instead as aninfusion at a rate of about 2 mgs. per minute to a total dose of about50 mgs. to about 300 mgs.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of metaprolol to treat a condition. Adult oral dosage forms(e.g., tablets) of metoprolol may include about 100 mgs. to 450 mgs. aday, taken as a single dose or in divided doses. For example,embodiments may include administering about 50 mgs. about every sixhours for about 24 hours or more and then about 100 mgs. two times a dayfor about 1 to about 3 months or more, e.g., from about 1 to about 3years or more. Embodiments may include administering long-acting adultoral dosage forms (extended-release tablets) that may include up toabout 400 mgs. once a day. Adult injection dosage form may include about5 mgs. every two minutes for about three doses.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of nadolol (e.g., available under the brand name CORGARD) totreat a condition. Embodiments ay include administering adult oraldosage forms (e.g., tablets) of nadolol that may include about 40 mgs.to about 320 mgs. once a day.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of oxprenolol to treat a condition. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of oxprenolol(short-acting) that may include about 20 mgs. three times a day.Embodiments may include administering adult long-acting oral dosageforms (extended-release tablets) that may include about 120 mgs. toabout 320 mgs. once a day.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of pentbutolol to treat a condition. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of penbutolol thatmay include about 20 mgs. once a day.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of pindolol to treat a condition. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of pindolol thatmay include about 5 mgs. two times a day—up to about 60 mgs. a day.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of propranolol to treat a condition. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of propranololthat may include, for regular (short-acting) oral dosage forms (tabletsand oral solution), about 80 mgs. to about 320 mgs. a day taken in, two,three, or four divided doses up to about 640 mgs./day in certainembodiments. Embodiments may also include about 10 mgs. to about 40 mgs.three or four times a day for an adult and about 500 micrograms (0.5mgs.) to about 4 mgs. per kilogram of body weight a day taken in divideddoses for children. Embodiments may include administering long-actingadult oral dosage forms (extended-release capsules) that may includeabout 80 mgs. to about 320 mgs. once a day up to about 640 mgs. once aday. Embodiments may include administering adult injection dosage formsthat range from about 1 mg. to about 3 mgs. given at a rate not greaterthan about 1 mg per minute. The dose may be repeated after about twominutes and again after about four hours if needed. Children may beadministered about 10 mgs. to about 100 micrograms (0.01 to 0.1 mg) perkilogram of body weight given intravenously about every six to eighthours.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of sotalol to treat a condition. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of sotalol thatmay include about 80 mgs. two times a day up to about 320 mgs. per daytaken in two or three divided doses.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of timolol (e.g., available under the brand name BLOCADREN) totreat a condition. Embodiments may include administering adult oraldosage forms (e.g., tablets) of timolol that may include about 10 mgs.two times a day up to about 60 mgs. per day taken as a single dose or individed doses. For example, up to 30 mgs. once a day or in divideddoses.

As noted above, in addition to an effective amount of at least onebeta-blocker, an effective amount of at least one non beta-blocker agentmay also be administered to a subject to treat a condition. As notedabove, the dose of non beta-blocker will be different for differentsubject, conditions treated, etc. The following embodiments describeaverage doses of various non beta-blocker agents that may be employed inthe practice of the subject invention and may vary. Such are forexemplary purposes only and are in no way intended to limit the scope ofthe invention. For example, the number of capsules or tablets,teaspoonfuls of solution, and the like, administered depends at least inpart on the strength of the particular non beta-blocker administered.Furthermore, the number of doses administered each day, the time allowedbetween doses, and the length of time a subject takes the medicine,etc., depend on the condition being treated, i.e., the condition forwhich a subject is taking the non beta-blocker. A person of ordinaryskill in the art will be able without undue experimentation, havingregard to that skill and this disclosure, to determine a therapeuticallyeffective amount of a particular non beta-blocker agent for practice ofthis invention. For example, embodiments may include dosagesconventionally administered for the particular non beta-blockeremployed, where such dosages are known in the art.

Aldosterone Antagonists

Embodiments may include administering an aldosterone antagonist to treata condition in accordance with the subject invention. For example,embodiments may include administering adult oral dosage forms (e.g.,tablets) of spironolactone that may range from about 50 mgs. to about400 mgs. daily. Embodiments may include administering adult oral dosageforms (e.g., tablets) of eplerenone that may range from about 50 mgs. toabout 100 mgs. daily.

Angiotensin II Receptor Blockades:

Embodiments may include administering an angiotensin II receptorblockade to treat a condition in accordance with the subject invention.Such embodiments may include administering an adult oral dosage form ofcandesartan (e.g., ATACAND) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 2 mgs. to about 32mgs. of candesarten daily (i.e., for a 24 hour interval), e.g., about 16mgs. daily. Embodiments may include administering adult oral dosageforms of irbersarten (e.g., AVAPRO) to a subject to treat a condition.Exemplary treatment protocols may include administering about 75 mgs. toabout 100 mgs. or more, e.g., up to about 300 mgs., of irbersartendaily. Embodiments may include administering adult oral dosage forms oflosartan (e.g., COZAAR) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 25 mgs. to about 50mgs. or more, e.g., 100 milligrams, of losarten orally once daily ortwice daily. Embodiments may include administering adult oral dosageforms of telmisartin (e.g., MICARDIS) to a subject to treat a condition.Exemplary treatment protocols may include administering about 20 mgs. toabout 80 mgs. of telmisartin daily. Embodiments may includeadministering adult oral dosage forms of valsartan (e.g., DIOVAN) to asubject to treat a condition. Exemplary treatment protocols may includeadministering about 20 mgs. to about 80 mgs. of valsarten once daily.Embodiments may include administering adult oral dosage forms ofeprosarten (e.g., TEVETAN) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 400 mgs. to about800 mgs. of eprosarten once daily or twice daily.

Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors):

Embodiments may include administering an ACE inhibitor to a subject totreat a condition in accordance with the subject invention. Such mayinclude administering adult oral dosage forms of captropil (e.g.,CAPOTEN) to a subject to treat a condition. Exemplary treatmentprotocols may include administering about 12.5 mgs. to about 50 mgs. ofcaptropil over about 8 to about 12 hours. Embodiments may includeadministering adult oral dosage forms of enalapril (e.g., VASOTEC) to asubject to treat a condition. Exemplary treatment protocols may includeadministering about 5 mgs. to about 20 mgs. of enalapril once daily.Embodiments may include administering adult oral dosage forms offosinopril (e.g., MONOPRIL) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 10 mgs. to about 80mgs., e.g., about 20 mgs. to about 40 mgs., of fosinopril daily.Embodiments may include administering adult oral dosage forms oflisinopril (e.g., PRINIVIL) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 10 mgs. to about 80mgs., e.g., about 20 mgs. to about 40 mgs., of lisinopril daily.Embodiments may include administering adult oral dosage forms ofmoexipril (e.g., UNIVASC) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 3.75 mgs. to about15 mgs., e.g., 7.5 mgs. of moexipril daily. Embodiments may includeadministering adult oral dosage forms of quinaapril (e.g., ACCUPRIL) toa subject to treat a condition. Exemplary treatment protocols mayinclude administering about 10 mgs. to about 80 mgs, e.g., about 20mgs., of quinapril once daily. Embodiments may include administeringadult oral dosage forms of ramipril (e.g., ALTACE) to a subject to treata condition. Exemplary treatment protocols may include administeringabout 2.5 mgs. to about 20 mgs. of ramipril daily. Embodiments mayinclude administering adult oral dosage forms of trandolapril (e.g.,MAVIK) to a subject to treat a condition. Exemplary treatment protocolsmay include administering about 1 mg. to about 4 mgs., e.g., about 2mgs., of trandolapril daily.

Statins

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of a statin to treat a condition in accordance with the subjectinvention. For example, embodiments may include administering adult oraldosage forms (e.g., tablets) of atorvastatin (e.g., available under thebrand name Lipitor) that may range from about 0.5 mgs. to about 80 mgs.daily. Embodiments may include administering adult oral dosage forms(e.g., tablets) of cerivastatin (e.g., available under the brand nameBaycol) that may range from about 0.2 mgs. to about 0.3 mgs. daily.Embodiments may include administering adult oral dosage forms (e.g.,tablets) of fluvastatin (e.g., available under the brand name lescoL)that may range from about 20 mgs. to about 80 mgs. daily. Embodimentsmay include administering adult oral dosage forms (e.g., tablets) oflovastatin (e.g., available under the brand name Mevacor) that may rangefrom about 10 mgs. to about 80 mgs. daily. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of prevastatin(e.g., available under the brand name Pravachol) that may range fromabout 10 mgs. to about 40 mgs. daily. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of simvastatin(e.g., available under the brand name Zocor) that may range from about 5mgs. to about 40 mgs. daily.

Triglycerides Lowering Drugs:

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of a triglycerides lowering drug to treat a condition inaccordance with the subject invention. For example, embodiments mayinclude administering adult oral dosage forms (e.g., tablets) offenofibrate (e.g., available under the brand name TRICOR) that may rangefrom about 65 mgs. to about 200 mgs. daily. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of genfibrozil(e.g., available under the brand name LOPID) that may range from about1200 mgs. total given as about 600 mgs. two times per day (e.g., every12 hours).

Niacin

Embodiments may include administering niacin to treat a condition inaccordance with the subject invention. For example, dosing may includeadministering by mouth about 2 mgs. to about 6 mgs. total, e.g., asgiven as about 1 mg. to about 2 mgs. twice per day or three times perday.

Anti-Diabetes Agents:

Embodiments may include administering an anti-diabetes drug to treat acondition in accordance with the subject invention. For example,embodiments may include administering adult oral dosage forms (e.g.,tablets) of acarbose (e.g., available under the brand name PRECOSE) thatmay range from about 25 mgs. to about 300 mgs. for an eight hourinterval. Embodiments may include administering adult oral dosage forms(e.g., tablets) of glimepiride(e.g., available under the brand nameAMARYL) that may range from about 1 mg. to about 2 mgs. daily.Embodiments may include administering adult oral dosage forms (e.g.,tablets) of glyburide (e.g., available under the brand names MICRONASE,DIABETA) that may range from about 1.5 mgs. to about 5 mgs. daily.Embodiments may include administering adult oral dosage forms (e.g.,tablets) of metformin (e.g., available under the brand name GLUCOPHASGE)that may range from about 500 mgs. to about 850 mgs. for an 8 to 24 hourinterval. Embodiments may include administering adult oral dosage forms(e.g., tablets) of miglitol (e.g., available under the brand nameGLYCET) that may range from about 25 mgs. to about 100 mgs. for an 8hour interval. Embodiments may include administering adult oral dosageforms (e.g., tablets) of pioglitazone (e.g., available under the brandname ACTOS) that may range from about 15 mgs. to about 40 mgs. daily.Embodiments may include administering adult oral dosage forms (e.g.,tablets) of repaglinide (e.g., available under the brand name PRANDIN)that may range from about 0.5 mgs. to about 4.0 mgs. 3 times per day.Embodiments may include administering adult oral dosage forms (e.g.,tablets) of rosiglitazone (e.g., available under the brand name AVANDIA)that may range from about 4 mgs. to about 8 mgs. daily.

Immunomodulators:

Embodiments may include administering an immunomodulator to treat acondition in accordance with the-subject invention. For example,embodiments may include administering adult dosage form of interferonbeta-1B (e.g., available under the brand name BETASERON), where dosingmay include administering about 0.25 mg. subcutaneously every other day.Embodiments may also include administering adult dosage form ofinterferon alfa-2A (e.g., available under the brand name ROFERON-A),where dosing may include administering about 3 million units to about 36million units per day IM/SC to about 3 million units to about 36 millionunits 3 times per week (3 million units (1 ml); 6 million units/ml (3ml); 0 million units/ml (0.9 ml), 3 ml); 36 million units/ml (1 ml)).Embodiments may also include administering adult dosage form ofinterferon alfa-2B (e.g., available under the brand name INTRON-A),where dosing may include administering about 1 to about 30 millionunits/M2 IM/SC three times per week (3 million units (0.5 ml); 5 millionunits (0.5 ml); 10 million units (1 ml); 25 million units powder forinjection: 18 million units and 50 million units). Embodiments may alsoinclude administering adult dosage form of interferon alfa-2B andribavirin combination pack (e.g., available under the brand nameREBETRON), where dosing may include administering INTRON A at about 3million units subcutaneously three times per week and about 500 mgs. toabout 600 mgs. of ribavirin twice daily. Embodiments may also includeadministering adult dosage form of interferon alfa-N3 (e.g., availableunder the brand name ALFERON N), where dosing may include administeringabout 250,000 units (0.05 ml) twice weekly (5 million units (1 ml)).Embodiments may also include administering adult dosage form ofinterferon beta-1A (e.g., available under the brand name AVONEX), wheredosing may include administering about 30 micrograms IM once weekly(reconstitute with 1.1 ml of diluent).

Nicotine:

Embodiments may include administering nicotine to treat a condition inaccordance with the subject invention. For example, embodiments mayinclude administering nicotine in the form of chewing gum, e.g., fromabout 2 mgs. to about 4 mgs. dosage strength). Embodiments may includeadministering nicotine as an inhalant (e.g., about 4 mgs. percartridge), nasal spray (e.g., each actuation of nicotine nasal spraymay deliver about 0.5 mgs. nicotine), or as a transdermal system. Forexample, dosing schedules (mg/day) of nicotine transdermal systems mayinclude a patch duration of about 24 hours and dosing schedule of about7 mgs. to about 22 mgs. for about 2 to about 6 weeks; a patch durationof about 16 hours and a dosing schedule of about 15 mgs. for about 4 toabout 12 weeks. Each dosing schedule may be followed by a reduced dosingschedule.

Sympathomimetics:

Embodiments may include administering a sympathomimetic to treat acondition in accordance with the subject invention. For example,embodiments may include administering trimethaphan via an I.V., e.g.,about 0.1 mgs. to about 1.0 mgs./minute, up to about 15 mgs. per minute.Embodiments may include orally administering clondine at about 0.1 mgs.to about 2.4 mgs. daily. Embodiments may include orally administeringreserpine at about 10 mgs. to about 20 mgs. daily. Embodiments mayinclude orally administering guanethidine at about 10 mgs. to about 50mgs. daily.

Antihistamines

Embodiments may include administering adult oral dosage forms of anantihistamine to treat a condition in accordance with the subjectinvention. For example, embodiments may include administering adult oraldosage forms (e.g., tablets) of BENADRYL at about 25 mgs. to about 50mgs. three to four times daily. Nighttime dosage may include about 50mgs. at bedtime.

Cholinergics:

Embodiments may include administering a cholinergic to treat a conditionin accordance with the subject invention. For example, embodiments mayinclude administering bethanechol at about 10 mgs. to about 50 mgs. fourtimes per day or three times per day. Embodiments may includeadministering methacoline as an inhaled aerosol at about 0.02 to about25.0 mg/mL. Embodiments may include orally administering about 30 mgs.cevimeline three times per day.

Acetylcholinesterase Inhibitors:

Embodiments may include administering an acetylcholinesterase inhibitorto treat a condition in accordance with the subject invention. Forexample, embodiments may include administering about 0.1 ml. to about0.8 ml via I.V. edrophonium or about 1 ml. of a 1:20000solution (0.5mg.) of neostigmine intramuscularly (IM) or subcutaneously (SC).Embodiments may also include orally administering about 5 mg ofdonepezil to about 10 mgs./day. Embodiments may also includeadministering about 1 to about 2 g of pralidoxime, e.g., as an infusionin 100 mL of saline, over about a 15 to 30 minute period, via I.V. About16 mgs to about 32 mgs. of galanthamine may be administered orally twiceper day. Physostigmine may be administered intravenously orintramuscularly e.g., about 0.5 mgs. to about 2 mgs. Rivastigmine may beorally administered, e.g., about 3 mgs. to about 6 mgs. two times perday.

Magnesium and Magnesium Sulfates:

Embodiments may include administering magnesium to treat a condition inaccordance with the subject invention. For example, a dose may includeabout 0.3 to about 1.0 meq mg/kg daily via an I.V.

Calcium Channel Blockers:

Embodiments may include administering a calcium channel blocker to treata condition in accordance with the subject invention. Embodiments mayinclude orally administering amlodipine besylate (e.g., available underthe brand name NORVASC), e.g., about 5 mgs. to about 20 mgs. daily;diltiazem hydrochloride (e.g., available under the brand names CARDIZEMCD, CARDIZEM SR, DILACOR XR, TIAZAC) at about 30 mgs. to about 360 mgs.four times per day (for example 180 mgs. to about 360 mgs. divided intofour times per day); felodipine plendil at about 2.5 mgs. to about 10mgs. daily; isradipine (e.g., available under the brand names DYNACIRC,DYNACIRC CR) at about 2.5mgs. daily; nicardipine (e.g., available underthe brand name CARDENE SR) at about 20 mgs. to about 40 mgs. three timesper day; nifedipine (e.g., available under the brand names ADALAT CC,PROCARDIA XL) at about 10 mgs. three times per day; nisoldipine (e.g.,available under the brand name SULAR) at about 10 mgs. to about 20 mgs.daily; and verapamil hydrochloride (e.g., available under the brandnames CALAN SR, COVERA HS, ISOPTIN SR, VERELAN) at about 40 mgs. threetimes per day.

Muscarinics:

Embodiments may include administering a muscarinic to treat a conditionin accordance with the subject invention. For example, embodiments mayinclude administering about 5 mgs. of pilocarpine by mouth to a subjectfour times per day, up to about 30 mgs./day.

Sodium Channel Blockers:

Embodiments may include administering a sodium channel blocker to treata condition in accordance with the subject invention. For example,embodiments may include administering about 150 mgs. of propafenone bymouth every 8 hours (450 mgs./day) up to about 300 mgs. every 8 hours(90 mgs./day). Embodiments may also include administering about 50 mgs.to about 100 mgs. of flecainide by mouth about every 12 hours up toabout 400 mgs./day. Embodiments may also include administering about 400mgs. to about 2400 mgs. of tocainide by mouth about every 8 hours.Embodiments may also include administering about 100 mgs. to about 200mgs. of phenytoin by mouth three times per day. Embodiments may alsoinclude administering about 10-30 mgs of about 1% to about 2% lidocaineIM (the maximum individual dosage typically should not exceed about 4.5mg/kg of body weight and generally the maximum total dose should notexceed about 300 mgs.). Embodiments may also include administering about150 mgs. to about 300 mgs. of dispoyramide by mouth about every 6 hoursto about every 12 hours, up to about 1600 mgs. per day. Embodiments mayalso include administering quinidine (e.g., available under the brandname QUINAGLUTE) at about two tablets (648 mgs.; 403 mgs. of quinidinebase) of QUINAGLUTE by mouth about every 8 hours.

Glucocorticoid Receptor Blockers:

Embodiments may include administering a glucocorticoid receptor blockerto treat a condition in accordance with the subject invention. Forexample, embodiments may include administering mifepristone my mouth atabout 400 micrograms to about 600 mgs.

Peripheral Andrenergic Inhibitors:

Embodiments may include administering a peripheral andrenergic inhibitorto treat a condition in accordance with the subject invention. Forexample, embodiments may include administering about 5 mgs. to about 75mgs. of guanadrel (e.g., available under the brand name HYLOREL) bymouth e.g., about 5 mgs. two times per day, about 20 to about 75 mgs.per day in divided doses. Embodiments may also include administeringabout 10 mgs. to about 50 mgs. or more per day of guanethidinemonosulfate (e.g., available under the brand name ISMELIN) by mouth.Embodiments may also include administering about 0.05 to about 1.5 mgs.once per day by mouth of reserpine (e.g., available under the brandnames SERPASIL, MECAMYLAMINE, HEXEMETHONIUM). Embodiments may alsoinclude administering about 2.5 mgs. of mecamylamine two times per dayby mouth.

Blood Vessel Dilators:

Embodiments may include administering a blood vessel dilator to treat acondition in accordance with the subject invention. For example,embodiments may include administering about 10 mgs. to about 50 mgs. ofhydralazine hydrocholoride (e.g., available under the brand nameAPRESOLINE) by mouth four times a day. Embodiments may also includeadministering about 5 mgs. to about 40 mgs. of minoxidil (e.g., e.g.,available under the brand name LONITEN) by mouth once per day.

Central Agonists:

Embodiments may include administering a central agonist to treat acondition in accordance with the subject invention. For example,embodiments may include administering about 250 mgs. of alpha methyldopa(e.g., available under the brand name ALDOMET) by mouth three times perday or about 500 mgs. to about 2 grams per day divided into 2 to 4doses. Embodiments may also include administering about 0.1 mgs. toabout 0.6 mgs. of clonidine hydrochloride (e.g., available under thebrand name CATAPRES) by mouth once per day. Embodiments may also includeadministering about 4 mgs. of guanabenz acetate (e.g., available underthe brand name WYTENSIN) by mouth two times per day (up to about 32 mgs.per day). Embodiments may also include administering about 1 mg. toabout 3 mgs. of guanfacine hydrochloride (e.g., available under thebrand name TENEX) by mouth once per day.

Combined Alpha and Beta-Blockers:

Embodiments may include administering a combined alpha and beta-blockerto treat a condition in accordance with the subject invention. Forexample, embodiments may include administering about 100 mgs. two timesper day of labetolol hydrochloride (e.g., available under the brandnames NORMODYNE, TRANDATE) by mouth up to about 400 mgs. per day.Embodiments may also include administering about 3.125 mgs. two timesper day of carvedilol (e.g., available under the brand name COREG) bymouth up to about 50 mgs. per day.

Alpha Blockers:

Embodiments may include administering an alpha and beta-blocker to treata condition in accordance with the subject invention. For example,embodiments may include administering about 1 mg once per day by mouthof doxazosin mesylate (e.g., available under the brand name CARDURA) upto about 16 mgs. per day. Embodiments may also include administeringabout 0.5 mgs. by mouth of prazosin hydrochloride (e.g., available underthe brand name MINIPRESS) two or three times per day (and may includeabout 6 to about 15 mgs. per day divided into 2 or 3 doses. Embodimentsmay also include administering about 1 mg. of terazosin hydrochloride(e.g., available under the brand name HYTRIN) by mouth once per day, upto about 5 mgs. per day.

Combination Diuretics:

Embodiments may include administering a combined diurentic to treat acondition in accordance with the subject invention. For example,embodiments may include administering about 1-2 tablets of amiloridehydrochloride+hydrochlorothiazide (e.g., available under the brand nameMODURETIC) once per day for tablets containing 5 mgs. of anhydrousamiloride HCl and 50 mgs. of hydrochlorothiazide). Embodiments may alsoinclude administering about 25 mgs. to about 50 mgs. once per day bymouth of spironolactone+hydrochlorothiazide (e.g., available under thebrand name ALDACTAZIDE). Embodiments may also include administeringabout 1 to 2 tablets one per day of triamterene+hydrochlorothiazide(e.g., available under the brand names DYAZIDE, MAXZIDE) for tabletscontaining 25 mgs. hydrochlorothiazide and 37.5 mgs. triaterene.

Potassium Sparing Diuretics:

Embodiments may include administering a potassium sparing diuretic totreat a condition in accordance with the subject invention. For example,embodiments may include administering about 5 mgs. to about 20 mgs. bymouth once per day of amiloride hydrochloride (e.g., available under thebrand name MIDAMAR). Embodiments may also include administering about 25mgs. to about 200 mgs. once per day by mouth of spironolactone (e.g.,available under the brand name ALDACTONE). Embodiments may also includeadministering about 1 to 2 tablets once per day of triamterene (e.g.,available under the brand name DYRENIUM) ) for tablets containing 25mgs. hydrochlorothiazide and 37.5 mgs. triaterene.

Nitrates:

Embodiments may include administering a nitrate to treat a condition inaccordance with the subject invention. For example, embodiments mayinclude administering isosorbide dinitrate (e.g., avalaible under thebrand name ISODIL) at about 50 to about 40 mgs. orally four times perday or 40 mgs. sustained release orally every 8 to 12 hours. Embodimentsmay also include administering isosorbide mononitrate (e.g., availableunder the brand names ISMO, MONOKET) at about 20 mgs. orally two timesper day and/or may include administering extended release initiallyabout 30 mgs. to about 60 mgs. orally once per day. Maximum of about 240mgs. /day. Embodiments may also include administering nitroglycerineointment, e.g., about 0.5 inches q8h and/or about 0.5 to about 2 inchesevery 4 to 6 hours, maximum 4 inches every 4 to 6 hours (0.5 inches isabout 7.5 mgs.). Embodiments may also include administering nitrobid,e.g., orally about 2.5 mgs. to about 9 mgs. 2 to 4 times per day.Embodiments may also include administering a nitroglycerin patch, e.g.,one patch each day applied and removed at bedtime.

Cyclic Nucleotide Monophosphodiesterase (“PDE”) Inhibitors:

Embodiments may include administering a cyclic nucleotidemonophosphodiesterase (“PDE”) inhibitor to treat a condition inaccordance with the subject invention. For example, embodiments mayinclude administering about 5 mgs. to about 20 mgs. once per day ofvardenafil (e.g., available under the brand name LEVITRA) by mouth.Embodiments may also include administering about 10 mgs. to about 20mgs. of tadalafil (e.g., available under the brand name CIALIS) orallyonce per day. Embodiments may also include administering about 25 mgs.to about 100 mgs. of sildenafil (e.g., available under the brand nameVIAGRA) orally once per day.

Alcohols:

Embodiments may include administering an alcohol to treat a condition inaccordance with the subject invention. For example, embodiments mayinclude administering about 200 mgs. orally four times per day or 0.5 toabout 1.0 ml per interspace for subarachnoid injections.

Vasopressin Inhibitors:

Embodiments may include administering a vasopressin inhibitor to treat acondition in accordance with the subject invention. For example,embodiments may include administering about up to about 6.75 mgadministered via IV of atosiban, e.g., 300 microgrns/min to about 100micrograms/min IV.

Oxytocin Inhibitors:

Embodiments may include administering an oxytoxin inhibitor to treat acondition in accordance with the subject invention. For example,embodiments may include administering about 0.25 to about IM ofterbutaline, typically not more than about 0.5 mgs. within a four hourperiod. Embodiments may also include administering about 50 microgramsper minute IV of ritodrine, maximum dosage of about 300 micrograms perminute.

Relaxin Hormone:

Embodiments may include administering a relaxin hormone to treat acondition in accordance with the subject invention. For example,embodiments may include administering 1 to 2 tablets of realxin by mouththree times per day fro tablets pf valerian/ayrvedic passion flowerblend (550 mgs.)

Renin Inhibitors:

Embodiments may include administering a rennin inhibitor to treat acondition in accordance with the subject invention. For example,embodiments may include administering Aliskiren by mouth at about 2 mgsto about 10 mgs./day.

Estrogen and Analogues (e.g., Estradiols) and Metabolites:

Embodiments may include administering estrogen and estrogen analoguesand estrogen metabolites to treat a condition in accordance with thesubject invention. For example, embodiments may include administeringabout 10 mgs. three times per day.

Gonadotropin-Releasing Hormone Inhibitors:

Embodiments may include administering a gonadotropin-releasing hormoneinhibitor to treat a condition in accordance with the subject invention.For example, embodiments may include administering leuprolide acetate atabout 65 mgs. SQ (subcutaneous) implant.

Vesicular Monoamine Transport (VMAT) Inhibitors:

Embodiments may include administering a VMAT inhibitor to treat acondition in accordance with the subject invention. For example,embodiments may include administering tetrabenazine by mouth at about150 mgs. to about 200 mgs. once per day. Embodiments may also includeadministering reserpine at about 50 micrograms to about 500 microgramsone time per day.

Dipeptidyl Peptidase (DP) IV Inhibitors (DP4 Inhibitors):

Embodiments may include administering a DP4 inhibitor to treat acondition in accordance with the subject invention. For example,embodiments may include administering LAF237 by mouth at about 25 mgs.to about 200 mgs. per day.

As noted above, embodiments may include employing an electrode todeliver a one or more beta-blockers to a subject. For example, anelectrode may be used that has a small port at its tip which isconnected to a reservoir or pump containing at least one beta-blocker.The beta-blocker delivery electrode may be implanted using any suitabletechnique such as surgical cut down, laproscopy, endoscopy, percutaneousprocedure, and the like. In certain embodiments a reservoir or pump mayalso be implanted in the subject's body. The beta-blocker deliveryelectrode, or other analogous device, may be controllable such that theamount of beta-blocker agent delivered, the rate at which thebeta-blocker may be delivered, and the time period over which thebeta-blocker may be delivered, etc., may be controllable and may beadjusted.

The actual area(s) of the sympathetic nervous system that may beinhibited with at least one beta-blocker will vary, and include, but arenot limited to, pre- and post ganglionic nerve fibers, ganglionicstructures, efferent and afferent nerve fibers, the hypothalamus,receptors on the hypothalamus, afferent autonomic nerves (sympatheticand parasympathetic) and hormonal receptors on the hypothalamus. Incertain embodiments, a given nerve fiber or the like may be inhibitedwith a beta-blocker in more than one area of the nerve fiber. Targetedareas of the sympathetic nervous system which may be inhibited ordampened in accordance with the subject invention include, but are notlimited to, internal carotid nerve and plexus, middle and superiorcervical sympathetic ganglion; vertebral ganglion; cervicothoracicganglion; sympathetic trunk; cervical cardiac nerves; cardiac plexus;thoracic aortic plexus; celiac ganglion; celiac trunk and plexus;superior mesenteric ganglion; superior mesenteric artery and plexus;intermesenteric plexus; inferior mesenteric ganglion; inferiormesenteric artery and plexus; superior hypogastric plexus; hypogastricnerves; vesical plexus; thoracic cardiac nerves; sympathetic trunk; 6ththoracic sympathetic ganglion; gray and white rami communicantes;greater, lesser and least splanchnic nerves; aorticorenal ganglion;lumbar splanchnic nerves; gray rami communicantes and sacral splanchnicnerves; and the like, or a combination of two or more of the above.

In certain embodiments, the subject methods may also include detecting,monitoring, observing, etc., information related to one or more aspectsof the autonomic nervous system such as a physical and/or chemicalaspect, e.g., activity, balance, etc., in at least a portion of theautonomic nervous system, e.g., in at least a portion of the sympatheticnervous system, and evaluating this information to determine the stateof the autonomic nervous system, e.g., the parasympathetic activityand/or sympathetic activity. Once the state of the autonomic nervoussystem is determined, it may be evaluated in regards to whether theautonomic nervous system is in an abnormal state or in need ofmodulation, e.g., whether activity in at least a portion of thesympathetic system needs to be decreased to increase the parasympatheticactivity/sympathetic activity ratio such that this analysis may beemployed as a “trigger” to providing pharmacological beta-blockermodulation of at least a portion of the autonomic nervous system whereinmodulation may not be otherwise performed unless the analysis determinedsuch is necessary.

Accordingly, collecting and evaluating this type of data and relating itto whether sympathetic activity modulation is required may be employedas a “trigger” to pharmacologically modulating at least a portion of theautonomic nervous system (e.g., performed prior to, during or followinga pharmacological beta-blocker regime) such that such data may indicatewhether, when, etc., pharmacological modulation is required—if at all.For example, in certain embodiments pharmacological modulation of atleast a portion of a subject's autonomic nervous system may notperformed unless one or more aspects of the autonomic nervous system aredetected and indicate such modulation is necessary. Any suitablephysical and/or chemical aspect or indicator of the autonomic nervoussystem may be employed, e.g., conduction, catecholamine levels, heartrate variability (“HRV”), action potentials, QT interval, as well aschronotropic, inotropic, and vasodilator responses. In certainembodiments, detection may include detecting the activity or function ofa particular organ or system under the control of the autonomic nervoussystem such as detecting rennin levels for the digestive system, oranalogous input parameter. Any suitable detection means may be employedto detect relevant information about the autonomic nervous system, aswill be described below.

In certain embodiments, a control feedback loop is provided. Forexample, during or following a particular beta-blocker treatmentregimen, the sympathetic activity (and/or parasympathetic activity) maybe monitored, observed, detected, etc., e.g., by sensing conduction inat least a portion of the sympathetic system by any suitable method.Other methods that may be employed to monitor the autonomic balanceinclude, but are not limited to, neurography, continuous or serialmeasurements of circulating catecholamine levels, chronotropic,inotropic, and vasodilator responses, heart rate variability (“HRV”),post-ganglionic action potentials, QT interval, and the like (see forexample Rang S, Wolf H, Montfrans G A, Karemaker J M. Non-invasiveassessment of autonomic cardiovascular control in normal pregnancy andpregnancy-associated hypertensive disorders: a review. J Hypertens2002;20(11):2111-9). For example, a sensor suitable for detecting nervecell or axon activity that are related to the autonomic nervous systemmay be implanted in a portion of a subject's body. A sensor may take theform of an electrode or the like. Signals received by such a sensor maybe amplified before further processing. A sensor may also take the formof a device capable of detecting nerve compound action potentials or maytake the form of a transducer that includes an electrode with an ionselective coating applied which is capable of directly transducing theamount of a particular transmitter substance or its breakdownby-products. Embodiments include utilizing a feedback system in such amanner that, if the desired decrease in sympathetic activity is notachieved, the same or a different beta-blocker protocol may beadministered. In other words, in utilizing such a feedback system, ifthe desired inhibition in activity or level of sympathetic activity isnot achieved, the same or a different protocol for inhibiting activitymay be performed. For example, in those instances where a differentprotocol is performed, one or more of the beta-blocker treatmentparameters may be modified, e.g., a different beta-blocker may beemployed instead or in addition to a first beta-blocker, the mode ofadministration may be altered, dosage may be altered, etc.

Certain embodiments include simultaneously monitoring, detecting,observing, etc., (i.e., in “real time”) the inhibition in the targetedarea or sympathetic activity (and/or parasympathetic activity) such thatan effective amount of at least one beta-blocker is administered to asubject and the result at least one sympathetic function is observedand/or monitored, e.g., at least once, continuously or intermittently orperiodically and in certain embodiments until the desired inhibition inactivity (parasympathetic activity/sympathetic activity balance) isobserved or longer. Still further, in many embodiments once the desiredautonomic nervous system modulation is achieved by at least inhibitingactivity in a portion of the sympathetic nervous system, pharmacologicalagents, including the same of different beta-blocker(s) or othertreatment options (surgery, ablation, etc.,) may be administered orotherwise performed thereafter at least one time and may be for a periodof time, e.g., one or more times, to maintain the desired state suchthat the subject methods may be repeated one or more times. For example,in certain embodiments beta-blockers may be administered for a period ofdays, weeks, months, or even years in certain embodiments.

As noted above, certain embodiments may include further modulating atleast a portion of the autonomic nervous system, i.e., in addition tomodulation with at least one beta-blocker. Such additional modulationmay include methods for inhibiting activity in at least a portion of theautonomic nervous system (e.g., in at least a portion of the sympatheticsystem and/or parasympathetic system) and/or stimulating or increasingactivity in at least a portion of the autonomic nervous system (e.g., inat least a portion of the sympathetic system and/or parasympatheticsystem). Suitable methods may employ pharmacological means, electricalmeans, and the like, depending on the desired result.

For example, inhibiting or down-regulating at least a portion of thesympathetic nervous system and/or parasympathetic system may beaccomplished in a number of ways. For example, inhibition ordown-regulation of activity may be achieved by surgically isolating aneffector structure (i.e., the target of the sympathetic and/orparasympathetic activity) from sympathetic and/or parasympatheticinnervation, i.e., surgically isolating an effector structure from oneor more sympathetic nerve fibers associated with it and/or from one ormore parasympathetic nerve fibers associated with it. Furthermore,sympathetic and/or parasympathetic nerves may be ablated, permanently orreversibly, by employing energy delivery devices or cryotherapy. Certainembodiments may employ cryoablation, thermoablation, microwave energy,focus ultrasound, magnetic fields including internal and externalmagnetic fields, laser energy, optical energy, radiofrequency energy,and the like. The sympathetic and/or parasympathetic system may also beinhibited or down-regulated or depressed by employing pacing mechanismssuch as implantable electrode-based pacing systems, externalmagnetic-based pacing system, and the like. Certain embodiments mayinclude inhibiting activity in at least a portion of the sympatheticand/or parasympathetic nervous system using transcutaneous electricalnerve stimulation (“TENS”) or transmagentic stimulation (“TMS”) (see forexample George, M. Stimulating the Brain. Sci Amer 2003 September).Still further, as noted above, pharmacological agents such as, but notlimited to, neurotoxins may be employed to disable sympathetic functionand/or parasympathetic function such that theparasympathetic/sympathetic ratio is increased temporarily orpermanently. In any event, activity in at least a portion of thesympathetic system and/or parasympathetic system, e.g., one or morenerve fibers associated with the sympathetic and/or parasympatheticsystem, may be inhibited by employing methods in addition to theadministration of at least one beta-blocker.

In certain embodiments, this inhibition may be achieved by employing anelectric energy applying device positioned directly on or about (i.e.,adjacent) the targeted area of the sympathetic system and/orparasympathetic system. Accordingly, embodiments may include increasingthe parasympathetic activity/sympathetic activity ratio by operativelypositioning an electric energy applying device on or about the one ormore sympathetic nerve fibers desired to be inhibited andelectrostimulating the target nerve fibers. Electric energy applyingdevice suitable for achieving this purpose, and methods of performingautonomic nervous system modulation using such devices are described,e.g., in copending U.S. application Ser. No. 10/661,368, entitled“Treatment of Conditions Through Electrical Modulation of the AutonomicNervous System”, the disclosure of which is herein incorporated byreference. In general, inhibiting sympathetic activity and/orparasympathetic activity using such an electric energy applying deviceor analogous device, once an electric energy applying device ispositioned in a suitable position on or about one or more targetedsympathetic and/or parasympathetic areas such as one or more sympatheticand/or parasympathetic nerve fibers, an electrical output, impulse orsignal is applied for a period of time sufficient to provide the desiredinhibition. This period of time will vary depending on the area (e.g.,the nerve fiber) being inhibited and the desired degree of inhibition,the condition being treated, etc.

As noted above, certain embodiments may include additional modulationthat may include methods for stimulating or increasing activity in atleast a portion of the autonomic nervous system (e.g., in at least aportion of the parasympathetic system). Accordingly, in certainembodiments activity in at least a portion of the parasympathetic systemmay be increased to modulate at least a portion of the autonomic nervoussystem. For example, any portion of the parasympathetic system, e.g.,one or more nerve fibers, may be pharmacologically modulated and/orelectrically stimulated to increase parasympathetic activity to providethe desired ratio of parasympathetic/sympathetic activity. In otherwords, activity in at least a portion of the parasympathetic nervoussystem may be increased by electrical stimulation such that at least aportion of the parasympathetic nervous system may be “up-regulated”.

Increasing activity in at least a portion of the parasympathetic systemand decreasing activity in at least a portion of the sympathetic system(e.g., with at least one beta-blocker) may be performed simultaneouslyor sequentially such that at least a portion of the parasympatheticnervous system may be modulated to increase activity therein prior orsubsequent to inhibiting activity in at least a portion of thesympathetic nervous system.

Increasing activity in, or up-regulating, at least a part of theparasympathetic system may be desired in instances where sympatheticactivity is higher than parasympathetic activity (i.e., there exists arelative sympathetic bias or dominance) and as such the subject methodsmay be employed to increase parasympathetic activity to a level above orrather to a level that is greater than sympathetic activity or may beemployed to modulate the differential between theparasympathetic-sympathetic systems such that the result of increasingparasympathetic activity may be a sympathetic bias, parasympathetic biasor may be an equalization of the two systems (i.e., the activities ofthe two systems are approximately equal-including equal), but thedifference between the parasympathetic-sympathetic systems may bemodulated, e.g., reduced or minimized or increased in certainembodiments. Accordingly, as described above, prior to practicing thesubject methods, the parasympathetic system may be high, lower orsubstantially equal to that of the sympathetic system and the net resultof the subject methods, whether they include beta-blocker therapy aloneor in combination with one or more additional therapies, may beparasympathetic activity that is higher or above that of sympatheticactivity, be parasympathetic activity that is less than or lower thanthat of sympathetic activity, or be parasympathetic activity that issubstantially equal to that of sympathetic activity, where activitylevels of interest may in terms of systemic levels or regional levels(i.e., localized). Accordingly, embodiments of the subject methods mayinclude increasing parasympathetic activity above that of sympatheticactivity and/or may be employed to modulate (increase or decrease) thedifferential between the two systems, but in any event is employed toincrease the ratio-of parasympathetic activity to sympathetic activity.

In certain embodiments, a sympathetic bias or dominance may be thenormal state, but the ratio of the two systems may be abnormal in asubject. Furthermore, increasing parasympathetic activity may also bedesired in instances where parasympathetic activity is higher than thesympathetic activity, but the differential between the two needs to bemodulated such as increased further, e.g., the sympathetic activity isnormal or above normal (i.e., abnormally high) and/or theparasympathetic activity is normal or below normal (i.e., abnormallylow) or above normal (i.e., abnormally low). For example, such instancesmay occur where a subject has normal or above normal parasympatheticfunction, but also has elevated sympathetic function. Other instancesinclude below normal parasympathetic function, but normal or elevatedsympathetic function, etc. It may also be desirable to increaseparasympathetic function in instances where the respective activities ofthe two system are analogous or approximately equal, including equal,prior to increasing activity in the parasympathetic system, but thelevel of one or both is abnormally high or abnormally low.

Accordingly, embodiments may include increasing activity in at least aportion of the parasympathetic system, e.g., one or more nerve fibersassociated with the parasympathetic system, using any suitable methods,such as methods analogous to those described above with respect toinhibiting activity in a portion of the autonomic nervous system, e.g.,by pharmacological methods and/or electric energy applying methods. Forexample, to increase activity in at least one area of theparasympathetic system such as a nerve fiber, an electric energyapplying device is operatively positioned directly on or about the oneor more parasympathetic nerve fibers to which an increase in activity isdesired.

The actual area(s) of the parasympathetic nervous system that may bemodulated, e.g., pharmacologically and/or electrically stimulated, willvary, and include, but are not limited to, pre- and post ganglionicnerve fibers, as well as ganglionic structures, efferent and afferentnerve fibers, synapses, etc., and combinations thereof in certainembodiments. In certain embodiments, activity in a given nerve fiber maybe modulated, e.g., electrically modulated, in more than one area of thenerve fiber. Targeted areas of the parasympathetic nervous system whichmay be modulated, e.g., electrically stimulated, in accordance with thesubject invention include, but are not limited to, the oculomotor nerve;facial nerve; glossopharyngeal nerve; hypoglossal nerve; trigeminalnerve, vagus nerve including the recurrent laryngeal branches of thevagus nerve, the pharyngeal and superior laryngeal branches of the vagusnerve, the cardiac branches of the vagus nerve, the anterior vagal trunkand the posterior vagal trunk; ciliary ganglion; pterygophalatineganglion; vidian nerve, pterygopalatine nerve, otic ganglion; chordatympsubmandibular ganglion; lingual nerve; submandibular ganglion;esophageal plexus; parasympathetic branch from inferior hypogastricplexus to descending colon; rectal plexus and pelvic planchnic nerves,or a combination of two or more of the above. For example, in certainembodiments activity may be increased in at least a portion of the vagusnerve and/or to the hypoglossal nerve and/or to the trigeminal nerve.

Certain embodiments may include providing long-term potentiation (“LTP”)of at least a portion of the parasympathetic nervous system. LTP may becharacterized as an enduring increase in synaptic efficacy resultingfrom high-frequency stimulation of an afferent (input) pathway. Forexample, long-term high frequency stimulation of at least a portion ofthe parasympathetic system may be employed to achieve parasympatheticbias or dominance. More specifically, rapid, intense electricalstimulation of presynaptic neurons associated with the parasympatheticsystem may be employed to evoke action potentials in one or morepostsynaptic neurons such that over time these synapses becomeincreasingly sensitive. This constant level of presynaptic stimulationeventually becomes converted into a larger postsynaptic output which maylast for minutes, hours, days, even weeks or more.

The above-described methods find use in a variety of differentapplications, representative types of which are described in greaterdetail below.

Utility

The subject methods find use in a variety of applications in which it isdesired to treat a subject for a condition caused by, affected orotherwise influences by an abnormality in the subject's autonomicnervous system. In such methods, at least a portion of a subject'sautonomic nervous system is pharmacologically modulated with at leastone beta-blocker to decrease sympathetic function in at least a portionof the sympathetic nervous system, e.g., to increase the parasympatheticactivity/sympathetic activity ratio. As indicated above, in manyembodiments of this type of application, the subject methods areemployed to treat a condition in the subject in order to achieve adesired therapeutic outcome. In certain embodiments, the condition beingtreated is a disease condition.

The subject methods find use in the treatment of a variety of differentconditions in which an abnormality in a subject's autonomic nervoussystem exists. By “treatment” is meant that at least an amelioration ofthe symptoms associated with the condition afflicting the subject isachieved, where amelioration is used in a broad sense to refer to atleast a reduction in the magnitude of a parameter, e.g. symptom,associated with the condition being treated. As such, treatment alsoincludes situations where the condition, or at least symptoms associatedtherewith, are completely inhibited, e.g. prevented from happening, orstopped, e.g. terminated, such that the subject no longer suffers fromthe condition, or at least the symptoms that characterize the condition.

A variety of subjects are treatable according to the subject methods. Inmany embodiments the subjects are “mammals” or “mammalian”, where theseterms are used broadly to describe organisms which are within the classmammalia, including the orders carnivore (e.g., dogs and cats), rodentia(e.g., mice, guinea pigs, and rats), and primates (e.g., humans,chimpanzees, and monkeys). In many embodiments, the subjects are humans.Human subject of both genders and at any stage of development (i.e.,neonates, infant, juvenile, adolescent, adult) may be treated accordingto the present invention. While the present invention may be used forthe treatment of a human subject, it is to be understood that thesubject methods may also be carried-out on other animal subjects suchas, but not limited to, mice, rats, dogs, cats, livestock and horses,e.g., for veterinary purposes, and for drug screening and drugdevelopment purposes. Accordingly, it is to be understood that anysubject in need of being treated according to the subject invention issuitable.

Moreover, suitable subjects of this invention include those who have andthose who have not previously been afflicted with a condition, thosethat have previously been determined to be at risk of suffering from acondition, and those who have been initially diagnosed or identified asbeing afflicted with or experiencing a condition.

As noted above, abnormalities in a subject's autonomic nervous systeminclude, but are not limited to, those characterized by an abnormallyhigh parasympathetic activity or abnormally low parasympathetic activityand/or an abnormally high sympathetic activity or abnormally lowsympathetic activity, where in certain embodiments the parasympatheticactivity and/or the sympathetic activity may be normal. For example,there are numerous conditions that the inventors of the subjectinvention have discovered are at least partially manifested by anabnormal sympathetic function, e.g., an abnormal balance of thesympathetic and parasympathetic functions of the autonomic nervoussystem, particularly those that manifest higher than normal (as definedby those seen in healthy individuals between the ages of about 20 toabout 25 years old) sympathetic function or ratio of sympatheticfunction to parasympathetic function, which may be treated in accordancewith the subject invention.

Examples of conditions that may be treated with the methods of thesubject invention include, but are not limited to, neurodegenerativeconditions including neurodegenerative diseases, e.g., Alzheimer'sdisease, Pick's disease, dementia, delirium, amyotrophic lateralsclerosis, and the like; neuroinflammatory conditions includingneuroinflammatory diseases, e.g., viral meningitis, viral encephalitis,fungal meningitis, fungal encephalitis, multiple sclerosis, charcotjoint; myasthenia gravis, and the like; orthopedic inflammatoryconditions including orthopedic inflammatory diseases, e.g.,osteoarthritis, inflammatory arthritis, regional idiopathicosteoporosis, reflex sympathetic dystrophy, Paget's disease,osteoporosis, and the like; lymphoproliferative conditions includinglymphoproliferative diseases, e.g., lymnphoma, lymphoproliferativedisease, Hodgkin's disease, inflammatory pseudomotor of the liver, andthe like; autoimmune conditions including automimmune diseases, e.g.,Graves disease, raynaud's, hashimoto's, takayasu's disease, kawasaki'sdiseases, arteritis, scleroderma, CREST syndrome, allergies, dermatitis,Henoch-schlonlein purpura, goodpasture syndrome, autoimmune thyroiditis,myasthenia gravis, Reiter's disease, lupus, and the like; inflammatoryconditions, e.g., ARDS, multiple sclerosis, rheumatoid arthritis,juvenile rheumatoid arthritis, juvenile chronic arthritis, and the like;infectious diseases, e.g., sepsis, viral and fungal infections, diseasesof wound healing, wound healing, tuberculosis, infection, AIDS, humanimmunodeficiency virus,-and the like; pulmonary conditions includingpulmonary diseases, e.g., tachypnea, fibrotic lung diseases such ascystic fibrosis and the like, interstitial lung disease, desquamativeinterstitial pneumonitis, non-specific interstitial pneumonitis,lymphocytic interstitial pneumonitis, usual interstitial pneumonitis,idiopathic pulmonary fibrosis, pulmonary edema, aspiration,asphyxiation, pneumothorax, right-to-left shunts, left-to-right shunts,respiratory failure, and the like; transplant-related conditions such astransplant related side effects such as transplant rejection,transplant-related tachycardia, transplant related renal failure,transplant related bowel dysmotility, transplant-related hyperreninemia,and the like; gastrointestinal conditions including gastrointestinaldiseases, e.g., hepatitis, xerostomia, bowel mobility, peptic ulcerdisease, constipation, ileus, irritable bowel syndrome, post-operativebowel dysmotility, inflammatory bowel disease, typhilitis, and the like;endocrine conditions including endocrine diseases, e.g., hypothyroidism,hyperglycemia, diabetes, obesity, syndrome X, insulin resistance,polycycstic ovarian syndrome (“PCOS”), and the like; genitourinaryconditions including genitourinary diseases, e.g., renal failure,hyperreninemia, hepatorenal syndrome, renal tubular acidosis, pulmonaryrenal syndrome, and the like; skin conditions including skin diseases,e.g., wrinkles, cutaneous vasculitis, psoriasis, and the like; agingassociated conditions including aging associated diseases, e.g., shydragers, multi-system atrophy, age related inflammation conditions,cancer, and the like; neurologic conditions including neurologicdiseases such as epilepsy, depression, schizophrenia, seizures, stroke,insomnia, cerebral vascular accident, transient ischemic attacks,stress, bipolar disorder, concussions, post-concussive syndrome,cerebral vascular vasospasm, central sleep apnea, obstructive sleepapnea, and the like; Th-2 dominant conditions including Th-2 dominantdiseases, e.g., typhilitis, osteoporosis, lymphoma, myasthenia gravis,lupus, and the like; conditions, including diseases, that cause hypoxia,hypercarbia, hypercapnia, acidosis, acidemia, such as acute pulmonaryembolism, sudden infant death syndrome (“SIDS”), sudden adult deathsyndrome (“SADS”), chronic pulmonary embolism, pleural effusion,cardiogenic pulmonary edema, non-cardiogenic pulmonary edema, acuterespiratory distress syndrome (ARDS), neurogenic edema, hypercapnia,academia, renal tubular acidosis, lung diseases that causes acidosis,and the like; pediatric-related conditions including pediatric-relateddiseases, e.g., respiratory distress syndrome, sudden infant deathsyndrome, hirschsprung disease, bronchopulmonary dysplasia, congenitalmegacolon, aganglionosis, and the like; OB-GYN conditions includingOB-GYN diseases, e.g., amniotic fluid embolism, menopausal mooddisorders, premenstrual mood disorders, pregnancy-related arrhythmias,fetal stress syndrome, fetal hypoxia, amniotic fluid embolism, and thelike; sudden death syndromes, e.g., sudden infant death syndrome, suddenadult death syndrome, and the like; fibrosis; post-operative recoveryconditions such as post-operative pain, post operative ileus,post-operative fever, post-operative nausea, and the like;post-procedural recovery conditions such as post-procedural pain, postprocedural ileus, post-procedural fever, post-procedural nausea, and thelike; chronic pain; trauma; and the like; disorders of thermoregulation,and the like. Other conditions may also be treated in accordance withthe subject invention, e.g., cyclic vomiting syndrome. Embodiments ofthe subject invention include treating one or more conditions,sequentially or at the same time, in accordance with the subjectinvention.

For example, conditions that promote maladaptive sympathetic bias may betreated with the subject invention. The inventors of the subjectinvention have realized that, unexpectedly, maladaptive sympathetic biasis a distinct syndrome that may be implicated in a number of fatal orpotentially fatal conditions. Normally, the sympathetic drive is anadaptive response to dynamic physiological demands of the body. Undercertain conditions, the response may become maladaptive. The inventorsof the subject invention have realized that dramatic impacts on thehealth and well-being of an individual, in certain instances, may berelated to acute sympathetic challenge in the context of backgroundchronic sympathetic bias.

Chronic sympathetic bias may occur in various situations. For example,it may occur when the normal sympathetic bias fails to correct aprecipitating respiratory or metabolic abnormality. The inventors of thesubject invention have realized that conditions such as sudden infantdeath syndrome (“SIDS”) and sudden adult death syndrome (“SADS”)including sudden death among pregnant women, as well as others, may fallin this category and thus are conditions that may be treated, or ratherprevented, by practicing the subject methods. Furthermore, sustainedsympathetic bias is also noted during pregnancy, presumably as anadaptive response. Some diseases, such as pheochromocytoma, areintrinsically adrenergic. Sympathetic bias may also be a maladaptivecomponent of the aging process attributable to an inexorable functionaldecline in autonomic regulatory systems. In the context of sympatheticbias, the inventors have realized that an acute sympathetic episode, asa centrally or peripherally mediated response to acute behavioral,metabolic, or physiologic stressors such as fear, injury, hypoxia,hypercarpnia, acidosis, sleep arousal, and physical activity, mayincrease the likelihood of certain conditions.

For example, conditions related to chronic or acute hypoxia,hypercarpnia and acidosis and other chronic conditions that disturb pO₂,pCO₂ and pH such as chronic obstructive pulmonary disease (“COPD”),primary pulmonary hypertension (“PPHTN”), secondary pulmonaryhypertension (“SPHTN”) and the like, may be treated in accordance withthe subject invention. Specifically, the inventors of the subjectinvention have discovered that excess sympathetic activity relative toparasympathetic activity elicited through, or rather a centrally orperipherally mediated response to, various changes in pO₂, pH and pCO₂,accounts for many of the physiological consequences of chronicconditions that disturb pO₂, pCO2 and pH. chronic conditions thatdisturb pO₂, pCO₂ and pH levels such as COPD, PPHTN, SPHTN, and thelike, e.g., by increasing the parasympathetic activity/sympatheticactivity ratio.

As noted above, the subject methods may be employed to treat or ratherprevent sudden infant death syndrome (“SIDS”) and sudden adult deathsyndrome (“SADS”), including sudden death amongst pregnant women. Inthis regard, the inventors of the subject invention have discovered thatin certain instances sympathetic bias may be implicated in SIDS andSADS.

More specifically, the inventors of the subject invention have realizedthat a maladaptive shift to sympathetic bias may be a key determinant ofSIDS. Heart rate variability (HRV) is often used as a measure ofautonomic balance. Decreased HRV, indicating sympathetic bias, has beenobserved in patients with central hypoventilation and in infants whohave later succumbed to SIDS (see for example Edner A, Katz-Salamon M,Lagercrantz H, Ericson M, Milerad J. Heart rate variability in infantswith apparent life-threatening events. Acta Paediatr. November2000;89(11): 1326-9). This finding is consistent with other conditionsof hypoxia such as respiratory distress syndrome and prenatal hypoxiawhich decrease HRV and induce tachycardia (see for example Aarimaa T,Oja R. Transcutaneous PO2, PCO₂ and heart rate patterns during normalpostnatal adaptation and respiratory distress. Early Hum Dev. January1988;16(1):3-11), both indicators of sympathetic bias. Infants whoexperience near-miss SIDS demonstrate tachycardia and decreased HRV (seefor example Reid G M. Sudden infant death syndrome: neonatal hypodynamia(reduced exercise level). Med Hypotheses. March 2001;56(3):280-5). Foodregurgitation and diaphoresis associated with SIDS may reflect excesssympathetic activity (see for example Kahn A, Groswasser J, Rebuffat E,Sottiaux M, Blum D, Foerster M, Franco P, Bochner A, Alexander M, BachyA, Richard P, Verghote M, Le Polain D, Wayenberg L 1992 Sleep andcardiorespiratory characteristics of infants victims of sudden death: aprospective case-control study. Sleep 15: 287-292; Guntheroth W G,Spiers P S. Thermal stress in sudden infant death: Is there an ambiguitywith the rebreathing hypothesis? Pediatrics. April 2001;107(4):693-8;Uchino M, Ishii K, Kuwahara M, Ebukuro S, Tsubone H. Role of theautonomic nervous system in emetic and cardiovascular responses inSuncus murinus. Auton Neurosci. Sep. 30, 2000;100(1-2):32-40).

Inciting causes of sympathetic bias may be manifold. Hyperthermia andfever, both of which have known associations with SIDS (see for exampleKahn A, Groswasser J, Rebuffat E,. Sottiaux M, Blum D, Foerster M,Franco P, Bochner A, Alexander M, Bachy A, Richard P, Verghote M, LePolain D, Wayenberg L 1992 Sleep and cardiorespiratory characteristicsof infants victims of sudden death: a prospective case-control study.Sleep 15: 287-292; Guntheroth W G, Spiers P S. Thermal stress in suddeninfant death: Is there an ambiguity with the rebreathing hypothesis?Pediatrics. April 2001;107(4):693-8) are hyperadregnergic states (seefor example Rowell L B. Hyperthermia: a hyperadrenergic state.Hypertension. May 1990;15(5):505-7). Infection and inflammation, whichare associated with SIDS (see for example Krous H F, Nadeau J M, Silva PD, Blackboume B D. A comparison of respiratory symptoms and inflammationin sudden infant death syndrome and in accidental or inflicted infantdeath. Am J Forensic Med Pathol. March 2003;24(1):1-8.), are alsopotential causes of sympathetic bias. In certain situations, theadaptive chemoreceptor-mediated sympathetic response of arousal andincreased respiration may fail to correct the underlying hypoxia,hypercapnia, and acidosis, leading to a maladaptive sympathetic bias.The association of prone sleeping position, obstructive sleep apnea, andother respiratory conditions with SIDS (see for example Kahn A,Groswasser J, Rebuffat E, Sottiaux M, Blum D, Foerster M, Franco P,Bochner A, Alexander M, Bachy A, Richard P, Verghote M, Le Polain D,Wayenberg L 1992 Sleep and cardiorespiratory characteristics of infantsvictims of sudden death: a prospective case-control study. Sleep 15:287-292; American Academy of Pediatrics, Task Force on Infant SleepPosition and Sudden Infant Death Syndrome. Changing concepts of suddeninfant death syndrome: implications for infant sleeping environment andsleep position. Pediatrics.2000; 105 :650-656; Hoffman H J, Damus K,Hillman L, Krongrad E. Risk factors for SIDS: results of the NationalInstitute of Child Health and Human Development SIDS CooperativeEpidemiological Study. Ann N Y Acad Sci 1988; 533: 13-30) may exemplifythis phenomenon. In infants with OSA, as with their adult counterparts,the sympathetic bias can exacerbate sleep disturbance and can triggerinsomnia (see for example Harrison G A. Stress, catecholamines, andsleep. Aviat Space Environ Med 1985; 56:651-653; Montagna P, Gambetti P,Cortelli P, Lugaresi E. Familial and sporadic fatal insomnia. LancetNeuro March 2003; 2(3):167-176.), leading to a pernicious cycle.

Sympathetic bias has an association with QT interval prolongation, arisk factor for sudden cardiac death in adults (see for example EspositoK, Marfella R, Gualdiero P, Carusone C, Pontillo A, Giugliano G,Nicoletti G, Giugliano D. Sympathovagal Balance, Nighttime BloodPressure, and QT Intervals in Normotensive Obese Women. Obes Res. May2003;11(5):653-9). Sympathetic bias may predispose infants to similarrisks. A significant association between prolonged QT interval and SIDSvictims or those who experienced apparent life-threatening event (ALTE)has been noted (see for example Goldhammer El, Zaid G, Tal V, Jaffe M,Abinader E G. QT dispersion in infants with apparent life-threateningevents syndrome. Pediatr Cardiol. November-December 2002;23(6):605-7;Schwartz P J, Stramba-Badiale M, Segantini A, et al. Prolongation of theQT interval and the sudden infant death syndrome. N Engl J Med.1998; 338:1709-1714). Various theories for this association have been proposed,including development-related abnormalities in cardiac sympatheticinnervation and genetic predisposition (see for example Stramba-BadialeM, Lazzarotti M, Schwartz P J. Development of cardiac innervation,ventricular fibrillation, and sudden infant death syndrome. Am J Physiol1992;263:H1514-H1522; Ackerman, M. J., Siu, B. L., Sturner, W. Q.,Tester, D. J., Valdivia, C. R., Makielski, J. C., Towbin, J. A. (2001).Postmortem Molecular Analysis of SCN5A Defects in Sudden Infant DeathSyndrome. JAMA 286: 2264-2269; Schwartz P J. Cardiac sympatheticinnervation and the sudden infant death syndrome: a possiblepathogenetic link. Am J Med 1976;60:167-172). The inventors of thesubject methods have realized that maladaptive sympathetic response isthe key determinant of SIDS, a broader view than that which had beenheld prior to the inventor's view.

The inventors of the subject invention have also realized that suddendeath precipitated by maladaptive sympathetic bias, similar to thoseseen in infants, may account for a proportion of SADS cases.

For example, while obviously multifactorial in mechanism, conditionssuch as constipation, insomnia, hypertension are endemic among the agedand are consistent with a broad physiologic bias towards sympatheticfunction. HRV and baroreflex sensitivity decreases with aging (see forexample Stratton J R, Levy W C, Caldwell J H, Jacobson A, May J,Matsuoka D, Madden K. Effects of aging on cardiovascular responses toparasympathetic withdrawal. J Am Coll Cardiol. Jun. 4,2003;41(11):2077-83), consistent with a shift to sympathetic bias. Theinventors have realized that, as in SIDS, some cases of SADS may reflectmaladaptive chemoreceptor response to hypoxia, hypercapnia, andacidosis, all of which are common conditions seen in the elderly due tomyriad of diseases. Examples of chronic diseases that exemplify thisphenomenon include, but are not limited to, renal failure, congestiveheart failure, chronic obstructive lung disease (“COPD”) and chronicpain (see for example Wiggers H, Botker H E, Egeblad H, Christiansen EH, Nielsen T T, Molgaard H. Coronary artery bypass surgery in heartfailure patients with chronic reversible and irreversible myocardialdysfunction: effect on heart rate variability. Cardiology.2002;98(4):181-5). Heightened sympathetic function is seen in many otherconditions including pheochromocytoma, autoimmune conditions, andcollagen vascular diseases (see for example Lagana B, Gentile R, VellaC, Giovani A, Tubani L, Mastrocola C, Baratta L, Bonomo L. Heart andautonomic nervous system in connective tissue disorders. Recenti ProgMed. December 1997;88(12)579-84; P. K. Stein, P. Nelson, J. N. Rottmanet al., Heart rate variability reflects severity of COPD in PiZalpha-l-antitrypsin deficiency. Chest 113 (1998), pp. 327-333). Morebroadly, the inventors have realized that attrition of parasympatheticfunction with aging may be an important but until now, unrecognized,culprit in generalized sympathetic bias of aging. For example, it hasbeen observed that QT interval lengthens with aging and other chronicconditions that promote sympathetic bias such as COPD (see for exampleWei, J. Y., Spurgeon, H. A. and Lakatta, E. G. (1984)Excitation-contraction in rat myocardium: alteration with adult aging.Am. J. Physiol. 246, H784-H791; Tukek T, Yildiz P, Atilgan D, Tuzcu V,Eren M, Erk O, Demirel S, Akkaya V, Dilmener M, Korkut F. Effect ofdiurnal variability of heart rate on development of arrhythmia inpatients with chronic obstructive pulmonary disease. Int J Cardiol.April 2003;88(2-3):199-206), putting the patient at increased risk offatal arrhythmias.

Still further, pregnant women may exhibit various signs of sympatheticbias such as hyperemesis, hypertension, and increased cardiac output,and as such may be treated in accordance with the subject invention.More specifically, the inventors of the subject invention have realizedthat sympathetic bias in pregnant women may be responsible for suddendeath in pregnant women. The shift to sympathetic bias may representadaptations to the physiologic and immunologic demands of gestation (seefor example Minagawa M, Narita J, Tada T, Maruyama S, Shimizu T, BannaiM, Oya H, Hatakeyama K, Abo T. Mechanisms underlying immunologic statesduring pregnancy: possible association of the sympathetic nervoussystem. Cell Immunol. Aug. 25, 1999;196(1):1-13). Pregnancy isassociated with QT prolongation, increased plasma catecholamine levels,and decreased HRV, similar to the other augmented sympathetic statesthat increase risk for sudden death (see for example Gowda R M, Khan IA, Mehta N J, Vasavada B C, Sacchi T J. Cardiac arrhythmias inpregnancy: clinical and therapeutic considerations. Int J Cardiol. April2003;88(2-3):129-33; N. D. Averyl, L. A. Wolfe, C. E. Amara, G. A. L.Davies, and M. J. McGrath. Effects of human pregnancy on cardiacautonomic function above and below the ventilatory threshold J ApplPhysiol 90: 321-328, 2001; Vol. 90, Issue 1, 321-328, January 2001).While an increase rate of sudden deaths from arrhythmias has been notedin pregnant women and has been attributed to hormonal influences (seefor example Wolbrette D. Treatment of arrhythmias during pregnancy. CurrWomens Health Rep. April 2003;3(2):135-9; Wolbrette D, Naccarelli G,Curtis A, Lehmann M, Kadish A. Gender differences in arrhythmias. ClinCardiol. February 2002;25(2):49-56), the subject inventors have realizedthat sympathetic excess of pregnancy may be a potential cause. The mostcommon manifestation of exaggeration of the normal sympathetic shift inpregnant women may be pre-eclampsia, which accounts for 80% of maternalmortality in developing countries (see for example Conz P A, Catalano C.Pathogenesis of pre-eclampsia. G Ital Nefrol. January-February2003;20(1):15-22). Measurement of post-ganglionic action potentialsreveal mean sympathetic activity to be three times higher inpre-eclamptic women compared with healthy pregnant women, and two timeshigher compared with the hypertensive non-pregnant women (see forexample Schobel H P, Fischer T, Heuszer K, Geiger H, Schmieder R E.Preeclampsia—a state of sympathetic overactivity. N Engl J Med 1996;335:1480-1485). HRV is reduced in pre-eclamptic women (see for exampleYang C C, Chao T C, Kuo T B, Yin C S, Chen H I. Preeclamptic pregnancyis associated with increased sympathetic and decreased parasympatheticcontrol of HR. Am J Physiol Heart Circ Physiol. April2000;278(4):H1269-73). Autonomic imbalance appears to particularlyaffect the central nervous system. Seizures, a common morbidity ofpre-eclampsia, and acute cerebral vasoconstriction, the most commoncause of mortality, may both be viewed as acute adrenergic phenomenon(see for example Novak V V, Reeves L A, Novak P, Low A P, Sharbrough WF. Time-frequency mapping of R-R interval during complex partialseizures of temporal lobe origin. J Auton Nerv Syst. Sep. 24,1999;77(2-3):195-202). Seizure is also a common presentation among theaged, with 25% of new cases of epilepsy diagnosed in the elderly (seefor example Stephen L J, Brodie M J. Epilepsy in elderly people. Lancet.Apr. 22, 2000;355(9213):1441-6).

The inventors of the subject invention have also discovered that manyconditions of aging are manifestations of sympathetic bias that isunmasked by withdrawal of autonomic function, particularly theparasympathetic system. For example, in regards to employing the subjectmethods in the treatment of aging associated conditions, the inventorsof the subject invention have realized that many clinical consequencesof aging are pleiotropic manifestations of the loss of parasympatheticfunction that occurs during post-reproductive senescence. The inventorsrealized that the loss of parasympathetic function unmasks the baselinesympathetic bias inherent in the end-organs, resulting in the familiarsigns of aging including tachycardia, constipation, insomnia, erectiledysfunction, fluid retention, and systemic inflammation. Theseconsequences in turn may contribute to many of the common diseasesassociated with aging including type-2 diabetes, Alzheimer's, cancer,and the like. Maintenance and restoration of parasympathetic functionmay enable upstream control over the deleterious aspects of inherentend-organ adrenergic bias.

More specifically, aging is marked by a compendium of physiologic andbiologic dysfunctions. The inventors of the subject invention haverealized that many seemingly unrelated consequences of aging are, atleast in part, manifestations of a single upstream phenomenon: anemergent sympathetic bias that is unmasked by loss of parasympatheticfunction during post-reproductive senescence and may be treated usingthe subject methods. Common symptomatic presentations among the elderlyinclude dysphagia, constipation, insomnia, anorexia, and the like. Thesesymptoms are the final common pathways of many different complexphysiologic disturbances and iatrogenic circumstances. These symptomsalso represent the classic organ-specific manifestations of excessadrenergic tone.

The inventors of the subject invention realized that if sympatheticexcess is the dominant biologic theme during senescence, the mechanismsmay be a loss of parasympathetic function. It is known that the vagusnerve shows decreased activity with age (see for example Tulppo M. P.,Makikallio T. H., Seppanen T., et al. Vagal modulation of heart rateduring exercise: effects of age and physical fitness. Am J PhysiolFebruary 1998; 274(2 Pt 2): H424-9). In the gastrointestinal system, theattrition of vagal and myenteric innervation has been noted withadvancing age (see for example Phillips R. J., Powley T. L. As the gutages: timetables for aging of innervation vary by organ in the Fischer344 rat. J Comp Neurol Jun. 4, 2000; 434(3):358-77). In the bladder,waning parasympathetic function has been noted and is one of the targetsfor treating dysfunctional bladder (see for example Anderson K. E.,Hedlund P. Pharmacologic perspective on the physiology of the lowerurinary tract. Urology November 2002; 60(5 Suppl 1):13-20). Accordingly,the subject methods may be employed to decrease or inhibit sympatheticactivity at least by administration of at least one beta-blocker andincrease or stimulate parasympathetic function.

Accordingly, the inventors of the subject invention realized that theend-organs of autonomic innervation are intrinsically sympathetic, thusresulting in the failure of the autonomic system to rebalance throughthe reduction of sympathetic tone-thereby offsetting the lostparasympathetic function-as vagal innervation generally wanes withaging. Accordingly, the inventors of the subject invention have realizedthat the end-organs of autonomic innervation are instrinsicallysympathetic, and in the absence of regulation, they exhibit tonicallyadrenergic activity that cannot be mitigated by a decrease in extrinsicsympathetic signal. As such, the inventors of the subject inventionrealized that the excess sympathetic tone is not likely to beattributable to generalized elevation in circulating catecholamines.Thus, the loss of parasympathetic function with aging may be viewed asthe unmasking the intrinsic sympathetic activity of end-organs, yieldingclinical consequences similar to those associated with aging.Accordingly, the inventors of the subject invention have realized thatsuch conditions may be treated with the subject invention, e.g., bydecreasing or inhibiting sympathetic activity at least by administrationof at least one beta-blocker and increasing or stimulatingparasympathetic function.

One of the most profound iterations of this theme may be the linkbetween the autonomic and immune systems, in particularly the linkbetween autonomic balance and Th-1/Th-2 balance. The superimposition oflifespan data on autonomic balance and Th-1//Th-2 balance (graph 1)demonstrates simultaneous peaking of relative parasympathetic and Th-1functions during reproductive adulthood, followed by a gradual loss ofthese functions during the ensuing senescence. Co-migration of thesefunctions over the lifespan suggests some link between the two functionsand the autonomic system may in part be responsible for governingTh-1/Th-2 balance both regionally and systemically through innervationsof various targets including the adrenal glands and lymphoid tissues.

The inventors of the subject invention have realized the dysregulationof inflammation resulting from the waning parasympathetic tone may beimplicated in the susceptibility of the elderly to many other conditionssuch as atherosclerotic disease, cancer, osteoporosis, viral infections,allergic conditions, and sepsis. As such, the subject methods may beemployed to modulating a subject's autonomic nervous to treataging-related conditions, including age-related disease conditions,e.g., by decreasing or inhibiting sympathetic activity at least byadministration of at least one beta-blocker and increasing orstimulating parasympathetic function.

Accordingly, as described above, the subject methods may be employed inthe treatment of a wide variety of conditions. For example, as describedabove, the subject methods may also be employed to treatneurodegenerative conditions including diseases. Branches of theautonomic nervous system that may be modulated in accordance with thesubject invention to treat neurodegenerative diseases includeparasympathetic nerve and ganglia such as, but not limited to one ormore of the vagus nerve, cranial nerve III, cranial nerve VII, cranialnerve IX, sphenopalatine ganglion, ciliary ganglion, submandibularganglion, otic ganglion and/or sympathetic nerve and ganglia such as,but not limited to one or more of cervical sympathetic ganglia.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat orthopedic inflammatorydiseases including diseases include parasympathetic nerve and gangliasuch as, but not limited to one or more of the vagus nerve and/orsympathetic nerve and ganglia such, but not limited to one or more ofthe spinal nerves (dorsal and ventral rami), postganglionic fibers tospinal nerves (innervating skin, blood vessels, muscle, adipose tissue)and sympathetic chain ganglia.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat inflammatory conditionsincluding diseases include parasympathetic nerve and ganglia such as,but not limited to one or more of the cranial nerve III, cranial nerveVII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion,submandibular ganglion, otic ganglion, vagus nerve, cardiac andpulmonary plexus, celiac plexus, hypogastric plexus and pelvic nervesand/or sympathetic nerve and ganglia such as, but not limited to one ormore of the cervical sympathetic ganglia, spinal nerves (dorsal andventral rami), postganglionic fibers to spinal nerves (innervating skin,blood vessels, sweat glands, erector pili muscle, adipose tissue),sympathetic chain ganglia, coccygeal ganglia, cardiac and pulmonaryplexus, greater splanchnic nerve, lesser splanchnic nerve, inferiormesenteric ganglion, celiac ganglion, superior mesenteric ganglion andlumber splanchnic nerves.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat lymphoproliferativeconditions including diseases include parasympathetic nerve and gangliasuch as, but not limited to one or more of the cranial nerve III,cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliaryganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiacand pulmonary plexus, celiac plexus, hypogastric plexus and pelvicnerves and/or sympathetic nerve and ganglia such as, but not limited toone or more of the cervical sympathetic ganglia, spinal nerves (dorsaland ventral rami), postganglionic fibers to spinal nerves (innervatingskin, blood vessels, sweat glands, erector pili muscle, adipose tissue),sympathetic chain ganglia, coccygeal ganglia, cardiac and pulmonaryplexus, greater splanchnic nerve, lesser splanchnic nerve, inferiormesenteric ganglion, celiac ganglion, superior mesenteric ganglion andlumber splanchnic nerves.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat inflammatory conditionsincluding diseases and infectious diseases include parasympathetic nerveand ganglia such as, but not limited to one or more of the cranial nerveIII, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion,ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve,cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, pelvicnerves and/or sympathetic nerve and ganglia such as, but not limited toone or more of the cervical sympathetic ganglia, spinal nerves (dorsaland ventral rami), postganglionic fibers to spinal nerves (innervatingskin, blood vessels, sweat glands, erector pili muscle, adipose tissue),sympathetic chain ganglia, coccygeal ganglia, cardiac and pulmonaryplexus, greater splanchnic nerve, lesser splanchnic nerve, inferiormesenteric ganglion, celiac ganglion, superior mesenteric ganglion andlumber splanchnic nerves.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat pulmonary conditionsincluding diseases include parasympathetic nerve and ganglia such as,but not limited to one or more of the vagus nerve, cardiac and pulmonaryplexus, celiac plexus, hypogastric plexus, pelvic nerves and/orsympathetic nerve and ganglia such as, but not limited to one or more ofthe cervical sympathetic ganglia, spinal nerves (dorsal and ventralrami), postganglionic fibers to spinal nerves (innervating skin, bloodvessels, sweat glands, erector pili muscle, adipose tissue), sympatheticchain ganglia, coccygeal ganglia, cardiac and pulmonary plexus, greatersplanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion,celiac ganglion, superior mesenteric ganglion and lumber splanchnicnerves.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat gastrointestinalconditions including diseases include parasympathetic nerve and gangliasuch as, but not limited to one or more of the vagus nerve, celiacplexus, hypogastric plexus, pelvic nerves and/or sympathetic nerve andganglia such as, but not limited to one or more of the sympathetic chainganglia, coccygeal ganglia, cardiac and pulmonary plexus, greatersplanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion,celiac ganglion, superior mesenteric ganglion and lumber splanchnicnerves.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat endocrine conditionsincluding diseases include parasympathetic nerve and ganglia such as,but not limited to one or more of the cranial nerve III, cranial nerveVII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion,submandibular ganglion, otic ganglion, vagus nerve, cardiac andpulmonary plexus, celiac plexus, hypogastric plexus, pelvic nervesand/or sympathetic nerve and ganglia such as, but not limited to one ormore of the cervical sympathetic ganglia, spinal nerves (dorsal andventral rami), postganglionic fibers to spinal nerves (innervating skin,blood vessels, sweat glands, erector pili muscle, adipose tissue),sympathetic chain ganglia, coccygeal ganglia, cardiac and pulmonaryplexus, greater splanchnic nerve, lesser splanchnic nerve, inferiormesenteric ganglion, celiac ganglion, superior mesenteric ganglion andlumber splanchnic nerves.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat genitourinary conditionsincluding diseases include parasympathetic nerve and ganglia such as,but not limited to one or more of the vagus nerve, cardiac and pulmonaryplexus, celiac plexus, hypogastric plexus, pelvic nerves and/orsympathetic nerve and ganglia such as, but not limited to one or more ofthe cervical sympathetic ganglia, spinal nerves (dorsal and ventralrami), postganglionic fibers to spinal nerves (innervating skin, bloodvessels, sweat glands, erector pili muscle, adipose tissue), sympatheticchain ganglia, coccygeal ganglia, cardiac and pulmonary plexus, greatersplanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion,celiac ganglion, superior mesenteric ganglion and lumber splanchnicnerves.

Branches of the autonomic nervous system that may-be modulated inaccordance with the subject invention to treat skin conditions includingdiseases include parasympathetic nerve and ganglia such as, but notlimited to one or more of the vagus nerve and/or sympathetic nerve andganglia such as, but not limited to one or more of the cervicalsympathetic ganglia such as, but not limited to one or more of thespinal nerves (dorsal and ventral rami), postganglionic fibers to spinalnerves (innervating skin, blood vessels, sweat glands, erector pilimuscle, adipose tissue), sympathetic chain ganglia and coccygealganglia.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat aging associatedconditions including diseases, including diseases includeparasympathetic nerve and ganglia such as, but not limited to one ormore of the cranial nerve III, cranial nerve VII, cranial nerve IX,sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, oticganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus,hypogastric plexus, pelvic nerves and/or sympathetic nerve and gangliasuch as, but not limited to one or more of the cervical sympatheticganglia, spinal nerves (dorsal and ventral rami), postganglionic fibersto spinal nerves (innervating skin, blood vessels, sweat glands, erectorpili muscle, adipose tissue), sympathetic chain ganglia, coccygealganglia, cardiac and pulmonary plexus, greater splanchnic nerve, lessersplanchnic nerve, inferior mesenteric ganglion, celiac ganglion,superior mesenteric ganglion and lumber splanchnic nerves.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat Th-2 dominant conditionsincluding diseases include parasympathetic nerve and ganglia such as,but not limited to one or more of the cranial nerve III, cranial nerveVII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion,submandibular ganglion, otic ganglion, vagus nerve, cardiac andpulmonary plexus, celiac plexus, hypogastric plexus, pelvic nervesand/or sympathetic nerve and ganglia such as, but not limited to one ormore of the cervical sympathetic ganglia, spinal nerves (dorsal andventral rami), postganglionic fibers to spinal nerves (innervating skin,blood vessels, sweat glands, erector pili muscle, adipose tissue),sympathetic chain ganglia, coccygeal ganglia, cardiac and pulmonaryplexus, greater splanchnic nerve, lesser splanchnic nerve, inferiormesenteric ganglion, celiac ganglion, superior mesenteric ganglion andlumber splanchnic nerves.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat neurologic conditionsincluding diseases include parasympathetic nerve and ganglia such as,but not limited to one or more of the cranial nerve III, cranial nerveVII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion,submandibular ganglion, otic ganglion, vagus nerve, cardiac andpulmonary plexus, celiac plexus, hypogastric plexus, pelvic nervesand/or sympathetic nerve and ganglia such as, but not limited to one ormore of the cervical sympathetic ganglia, spinal nerves (dorsal andventral rami), postganglionic fibers to spinal nerves (innervating skin,blood vessels, sweat glands, erector pili muscle, adipose tissue),sympathetic chain ganglia, coccygeal ganglia, cardiac and pulmonaryplexus, greater splanchnic nerve, lesser splanchnic nerve, inferiormesenteric ganglion, celiac ganglion, superior mesenteric ganglion andlumber splanchnic nerves.

Branches of the autonomic nervous system that may be modulated inaccordance with the subject invention to treat conditions, includingdiseases, that cause hypoxia, hypercarbia, acidosis, acidemia, includeparasympathetic nerve and ganglia such as, but not limited to one ormore of the cranial nerve III, cranial nerve VII, cranial nerve IX,sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, oticganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus,hypogastric plexus, pelvic nerves and/or sympathetic nerve and gangliasuch as, but not limited to one or more of the cervical sympatheticganglia, spinal nerves (dorsal and ventral rami), postganglionic fibersto spinal nerves (innervating skin, blood vessels, sweat glands, erectorpili muscle, adipose tissue), sympathetic chain ganglia, coccygealganglia, cardiac and pulmonary plexus, greater splanchnic nerve, lessersplanchnic nerve, inferior mesenteric ganglion, celiac ganglion,superior mesenteric ganglion and lumber splanchnic nerves.

Devices and Systems

The subject invention also includes devices and systems that may beemployed in the practice of the subject methods. The subject systems atleast include an effective amount of at least one beta-blocker. Thebeta-blocker may be in any suitable formulation or form. For example, asystem may include a beta-blocker composition for transdermaladministration, e.g., present as an active agent of a transdermal patch,film or the like, an oral dosage form, injection dosage form, etc.Additional pharmacological agents may also be included in systems of thesubject invention.

In certain embodiments, the subject systems may also include suitabledelivery means, dictated by the particular beta-blocker and/orpharmacological agent as describe above, e.g., the particular form ofthe agent such as whether the beta-blocker and/or other pharmacologicalagent is formulated into preparations in solid, semi-solid, liquid orgaseous forms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants and aerosols, and thelike, and the particular mode of administration of the agent, e.g.,whether oral, buccal, rectal, parenteral, intraperiactivityal,intradermal, transdermal, intracheal, intravaginal, endocervical,intrathecal, intranasal, intravesicular, on the eye, in the ear canal,etc. Accordingly, certain systems may include a suitable drug deliverydevice, e.g., a suppository applicator, syringe, I.V. bag and tubing,electrode, an implantable drug delivery device, an electric energyapplying device, and the like.

Systems may also include one or more devices for delivering, e.g.,implanting, a component such as a drug delivery device, anelectrosurgical device, and the like, to a target site of a subject suchas into the body cavity of a subject. For example, an endoscope,introducer needle, and the like, may be provided. Systems may alsoinclude one or more imaging or scanning apparatuses such as afluoroscope, CT scan, and the like.

The subject systems may also include an electric energy applying devicesuch that a system according to the present invention may include atleast one electrode for electrically modifying at least a portion of asubject's autonomic nervous system. In certain embodiments the electricenergy applying device is an implantable device, or at least certaincomponents such as one or more electrodes, may be implantable. Certainembodiments may include a plurality of electrodes, where some or all maybe the same or some or all may be different. For example, at least afirst electrode may be provide for electrically stimulating at least aportion of the parasympathetic system and at least a second electrodemay be provided for inhibiting activity in at least a portion of thesympathetic system. In certain embodiments, a “test” electrode, asdescribed above, may be included in a system. As noted above, such“test” electrodes may be a radiofrequency stimulating electrode. Stillfurther, one or more electrodes may be included in a system which,instead of or in addition to delivering electric impulses to at least aportion of the autonomic nervous system, delivers an autonomic nervoussystem pharmacological agent to at least a portion of the autonomicnervous system, e.g., may be used to deliver at least one beta-blocker.Included may be an energy source such as a battery or generator, wherein certain embodiments the energy source may be implantable, and mayalso include one or more leads or wires for coupling the one or moreelectrodes to an energy source.

A system for use in practicing the subject methods may also include asuitable detector for detecting one or more physical and/or chemicalaspects related to the autonomic nervous system. The detector at leastincludes data gathering means. Also provided may be data analysis meanswhere such may be a separate component from or integral with datagathering means, but in many embodiments is operatively coupled to datagathering means, e.g., integral with. In use, data related to one ormore aspects of the autonomic nervous system may be collected by datagathering means and forwarded to data analysis means which executessteps necessary to process and evaluate the collected data and determinewhether the autonomic nervous system is in need of electricalmodulation. Such evaluation may include comparing data to referencevalues, etc. When present, a detector (or data evaluation means ifseparate) may be operatively coupled to one or more other elements of agiven drug delivery means and/or electric energy applying device suchthat results of the determinations of autonomic modulation mayautomatically trigger (or cease) activation of drug delivery and/orelectrical energy to the autonomic nervous system. Suitable detectorsinclude any detector capable of gathering information about theautonomic nervous system and includes both invasive, minimally invasiveand non-invasive detectors where in certain embodiments a detector maybe an implantable detector. Suitable detectors include, but are notlimited to, those capable of collecting data regarding nerve conduction,circulating catecholamine levels, heart rate variability (“HRV”),post-ganglionic action potentials, QT interval, and the like andinclude, but are not limited to, MRI apparatuses, CT apparatus,neurography apparatuses, cardiovascular monitors, sensors includingelectrodes, etc.

Computer Readable Mediums and Programming Stored Thereon

Any part of the subject methods, e.g., detection, analysis andactivation/termination of drug delivery and/or electrical energyincluding selecting suitable drug delivery parameters and/or electricalparameters, may be performed manually or automatically. For example, thesubject invention may include suitable computing means such as suitablehardware/software for performing one or more aspects of the subjectmethods. For example, one or more aspects of the subject invention maybe in the form of computer readable media having programming storedthereon for implementing the subject methods. Accordingly, programmingaccording to the subject invention may be recorded on computer-readablemedia, e.g., any medium that can be read and accessed directly orindirectly by-a computer. Such media include, but are not limited to,computer disk or CD, a floppy disc, a magnetic “hard card”, a server,magnetic tape, optical storage such as CD-ROM and DVD, electricalstorage media such as RAM and ROM, and the hybrids of these categoriessuch as magnetic/optical storage media. One of skill in the art canreadily appreciate how any of the presently known computer readablemediums may be used to provide a manufacture that includes a recordingof the present programming/algorithm for carrying out theabove-described methodology. Thus, the computer readable media may be,for example, in the form of any of the above-described media or anyother computer readable media capable of containing programming, storedelectronically, magnetically, optically or by other means. As such,stored programming embodying steps for carrying-out some or all of thesubject methods may be transferred to a computer-operated apparatus suchas a personal computer (PC) or the like, by physical transfer of a CD,floppy disk, or like medium, or may be transferred using a computernetwork, server, or other interface connection, e.g., the Internet.

For example, the subject invention may include a computer readablemedium that includes stored programming embodying an algorithm forcarrying out some or all of the subject methods, where such an algorithmis used to direct a processor or series of processors to execute thesteps necessary to perform the task(s) required of it and as such incertain embodiments the subject invention includes a computer-basedsystem for carrying-out some or all of the subject methods. For example,such a stored algorithm may be configured to, or otherwise be capableof, directing a microprocessor to receive information directly orindirectly from data gathering means (i.e., information collected bydata gathering means about the autonomic nervous system) and processthat information to determine the state of the autonomic nervous system,e.g., the activity level of the parasympathetic system and/or thesympathetic system and even whether the autonomic nervous systemrequires modulation, e.g., if the parasympathetic activity is normal orabnormal and/or if sympathetic activity is normal or abnormal, and, ifso, the specifics of the modulation that may be required, e.g., to treata condition. The result of that processing may be communicated to auser, e.g., via audio and/or visual means, e.g., the algorithm may alsoinclude steps or functions for generating a variety of autonomic nervoussystem-profile graphs, plots, etc.

The algorithm may be configured to, or otherwise-be capable of,directing a microprocessor to activate, i.e., turn “on” and “off” a drugdelivery device, e.g., an implantable or external drug delivery deviceand/or an electric energy applying device for applying energy to atleast a part of the autonomic nervous system, e.g., in response to theabove-described determination of the state of the autonomic nervoussystem. For example, if it is determined that sympathetic activity needsto be decreased, the processor may direct a drug delivery device toprovide the appropriate amount of drug or otherwise execute a suitabledrug treatment regime to result in the desired action.

The subject invention may also include a data set of known or referenceinformation stored on a computer readable medium to which autonomicnervous system data collected may be compared for use in determining thestate of the autonomic nervous system. The data may be stored orconfigured in a variety of arrangements known to those of skill in theart.

Kits

Also provided are kits for practicing the subject methods. While thesubject kits may vary greatly in regards to the components included,typically, the kits at least include at least one beta-blocker in asuitable form. The subject kits may also include one or more otherpharmacological agents. The dosage amount of the one or morebeta-blockers and/or other pharmacological agents provided in a kit maybe sufficient for a single application or for multiple applications.Accordingly, in certain embodiments of the subject kits a single dosageamount of a beta-blocker and/or a single dosage of at least one another,different pharmacological agent is present.

In certain other embodiments, multiple dosage amounts of a beta-blockerand/or one other pharmacological agent may be present in a kit. In thoseembodiments having multiple dosage amounts of, e.g., at least onebeta-blocker, such may be packaged in a single container, e.g., a singletube, bottle, vial, and the like, or one or more dosage amounts may beindividually packaged such that certain kits may have more than onecontainer of a beta-blocker.

Suitable means for delivering one or more beta-blockers and/or otherpharmacological agents to a subject may also be provided in a subjectkit. The particular delivery means provided in a kit is dictated by theparticular beta-blocker and/or pharmacological agent employed, asdescribe above, e.g., the particular form of the beta-blocker and/orother agent such as whether the beta-blocker and/or otherpharmacological agent is formulated into preparations in solid,semi-solid, liquid or gaseous forms, such as tablets, capsules, powders,granules, ointments, solutions, suppositories, injections, inhalants andaerosols, and the like, and the particular mode of administration of theagent, e.g., whether oral, buccal, rectal, parenteral, intravaginal,endocervical, intrathecal, intranasal, intravesicular, on the eye, inthe ear canal, intraperiactivityal, intradermal, transdermal,intracheal, etc. Accordingly, certain systems may include a suppositoryapplicator, syringe, I.V. bag and tubing, electrode, transdermal patchor film, etc.

The subject kits also include instructions for how to practice thesubject methods and in particular how to administer the at least onebeta-blocker provided in the kit to treat a subject for a conditioncaused by an abnormality in the subject's autonomic nervous system bypharmacologically modulating at least a portion of the subject'sautonomic nervous system to decrease sympathetic activity to treat acondition. The instructions are generally recorded on a suitablerecording medium or substrate. For example, the instructions may beprinted on a substrate, such as paper or plastic, etc. As such, theinstructions may be present in the kits as a package insert, in thelabeling of the container of the kit or components thereof (i.e.,associated with the packaging or sub-packaging) etc. In otherembodiments, the instructions are present as an electronic storage datafile present on a suitable computer readable storage medium, e.g.CD-ROM, diskette, etc. In yet other embodiments, the actual instructionsare not present in the kit, but means for obtaining the instructionsfrom a remote source, e.g. via the internet, are provided. An example ofthis embodiment is a kit that includes a web address where theinstructions can be viewed and/or from which the instructions can bedownloaded. As with the instructions, this means for obtaining theinstructions is recorded on a suitable substrate.

Kits may also include an electric energy applying device, as describedabove. Accordingly, subject kits may include an electric energy applyingdevice such that they may include at least one electrode forelectrically modifying at least a portion of a subject's autonomicnervous system in accordance with the subject invention, as describedabove. In many embodiments, the electric energy applying device providedin a kit is an implantable device, or at least certain components suchas one or more electrodes, are implantable. Certain kits may include aplurality of electrodes, where some or all may be the same or some orall may be different. For example, certain kits may include at least afirst electrode for electrically stimulating at least apportion of theparasympathetic system and at least a second electrode for inhibitingactivity in at least a portion of the sympathetic system. In certainembodiments, a subject kit may include a “test” electrode, as describedabove such as a radiofrequency stimulating electrode. Still further, oneor more electrodes may be included in a kit which, instead of or inaddition to delivering electric impulses to at least a portion of theautonomic nervous system, delivers an autonomic nervous systempharmacological agent to at least a portion of the autonomic nervoussystem. Kits according to the subject invention typically also includean energy source such as a battery or generator, where in certainembodiments the energy source may be implantable, and may also includeone or more leads or wires for coupling the one or more electrodes to anenergy source.

Devices for delivering, e.g., implanting, an electrosurgical deviceand/or a drug delivery device to a target site of a subject such as intothe body cavity of a subject may also be included in the subject kits.For example, an endoscope, introducer needle, and the like may beprovided.

Some or all components of the subject kits may be packaged in suitablepackaging to maintain sterility. In many embodiments of the subjectkits, the components of the kit are packaged in a kit containmentelement to make a single, easily handled unit, where the kit containmentelement, e.g., box or analogous structure, may or may not be an airtightcontainer, e.g., to further preserve the sterility of some or all of thecomponents of the kit.

It is evident from the above discussion that the above describedinvention provides methods, system and kits for treating a subject for acondition caused by an autonomic nervous system abnormality in a subjectwhich are easy to use, effective, and which may be used to treat varietyof different conditions. As such, the subject invention represents asignificant contribution to the art.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

1. A method of treating a subject for a condition caused by an autonomicnervous system abnormality comprising modulating at least a portion ofsaid subject's autonomic nervous system by administering an effectiveamount of at least one beta-blocker to said subject to treat saidsubject for at least one of: neurodegenerative conditions;neuroinflammatory conditions; orthopedic inflammatory conditions;lymphoproliferative conditions; autoimmune conditions; inflammatoryconditions; infectious diseases, pulmonary conditions;transplant-related conditions, gastrointestinal conditions; endocrineconditions; genitourinary conditions selected from the group of renalfailure, hyperreninemia, hepatorenal syndrome and pulmonary renalsyndrome; aging associated conditions; neurologic conditions; Th-2dominant conditions; conditions that cause hypoxia; conditions thatcause hypercarbia; conditions that cause hypercapnia; conditions thatcause acidosis; conditions that cause academia, pediatric-relatedconditions; OB-GYN conditions, sudden death syndromes, fibrosis;post-operative recovery conditions; post-procedural recovery conditions;chronic pain; disorders of thermoregulation, cyclic vomiting syndromeand trauma.
 2. The method according to claim 1, wherein said modulationresults in a sympathetic bias in at least a portion of said autonomicnervous system.
 3. The method of claim 2, wherein said abnormality ischaracterized by a sympathetic bias.
 4. The method of claim 2, whereinsaid abnormality is characterized by a parasympathetic bias.
 5. Themethod according to claim 1, wherein said modulation results in aparasympathetic bias in at least a portion of said autonomic nervoussystem.
 6. The method of claim 5, wherein said abnormality ischaracterized by a sympathetic bias.
 7. The method of claim 5, whereinsaid abnormality is characterized by a parasympathetic bias.
 8. Themethod according to claim 1, wherein said modulating results in asubstantially equal parasympathetic and sympathetic functions in atleast a portion of said autonomic nervous system.
 9. The method of claim8, wherein said abnormality is characterized by a sympathetic bias. 10.The method of claim 8, wherein said abnormality is characterized by aparasympathetic bias.
 11. The method of claim 1, wherein saidabnormality is characterized by an abnormally high parasympatheticactivity.
 12. The method of claim 11, wherein said abnormality ischaracterized by an abnormally low sympathetic activity.
 13. The methodof claim 11, wherein said abnormality is characterized by normalsympathetic activity.
 14. The method of claim 11, wherein saidabnormality is characterized by an abnormally high sympathetic activity.15. The method of claim 11, further comprising decreasing saidabnormally high parasympathetic activity.
 16. The method of claim 1,wherein said abnormality comprises an abnormally low parasympatheticactivity.
 17. The method of claim 16, wherein said abnormality comprisesan abnormally low sympathetic activity.
 18. The method of claim 16,wherein said abnormality comprises normal sympathetic activity.
 19. Themethod of claim 16, wherein said abnormality comprises an abnormallyhigh sympathetic activity.
 20. The method of claim 10, furthercomprising increasing said parasympathetic activity.
 21. The method ofclaim 1, wherein said at least one beta-blocker is chosen from atenolol,betaxolol, bisoprolol, carvedilol, esmolol, labetalol, metoprolol,nadolol, pindolol, propranolol, sotalol, timolol, acebutalol,oxprenolol, carvedilol, and entbutolol.
 22. The method of claim 1,wherein said method comprises increasing the parasympatheticactivity/sympathetic activity ratio in at least a portion of saidsubject's autonomic nervous system.
 23. The method of claim 1, furthercomprising administering an effective amount of at least onenon-beta-blocker agent.
 24. The method of claim 23, wherein said atleast one non-beta-blocker agent is chosen from aldosterone antagonists;angiotensin II receptor blockades; angiotensin converting enzymeinhibitors; statins; triglycerides lowering drugs; niacin; anti-diabetesagents; immunomodulators; nicotine; sympathomimetics; cholinergics;acetylcholinesterase inhibitors; magnesium and magnesium sulfates,calcium channel blockers; muscarinics; sodium channel blockers;glucocorticoid receptor blockers; peripheral andrenergic inhibitors;blood vessel dilators; central agonists; combined alpha andbeta-blockers; alpha blockers; combination diuretics; potassium sparingdiuretics; nitrates; cyclic nucleotide monophosphodiesterase inhibitors;alcohols; catecholamines inhibitors; analgesics; neurotoxins;vasopressin inhibitors; oxytocin inhibitors; alcohol; relaxin hormone;renin inhibitors; estrogen; estrogen analogues; estrogen metabolites;progesterone inhibitors; testosterone inhibitors; gonadotropin-releasinghormone analogues; gonadotropin-releasing hormone inhibitors; vesicularmonoamine transport inhibitors; dipeptidyl peptidase IV inhibitors;antihistamines and melatonin.
 25. The method of claim 23, wherein saidat least one beta-blocker and at least one non-beta-blocker areconcomitantly administered in unit dosage form.
 26. The method of claim1, further comprising stimulating at least a portion of said subject'sautonomic nervous system.
 27. The method of claim 26, wherein saidstimulating comprises contacting at least a portion of said subject'sautonomic nervous system with at least one electrode and applyingelectrical energy to at least a portion of said subject's autonomicnervous system.
 28. The method of claim 1 wherein said at least onebeta-blocker is administered orally at least once a day to said subject.29. The method of claim 1, wherein said condition is a neurodegenerativecondition chosen from the group of: Alzheimer's disease, Pick's disease,dementia, delirium and amyotrophic lateral sclerosis.
 30. The method ofclaim 1, wherein said condition is a neuroinflammatory condition chosenfrom the group of: viral meningitis, viral encephalitis, fungalmeningitis, fungal encephalitis, multiple sclerosis, charcot joint andmyasthenia gravis.
 31. The method of claim 1, wherein said condition isan orthopedic inflammatory condition chosen from the group of:osteoarthritis, inflammatory arthritis, regional idiopathicosteoporosis, reflex sympathetic dystrophy, Paget's disease andosteoporosis.
 32. The method of claim 1, wherein said condition is alymphoproliferative condition chosen from the group of: lymphoma,lymphoproliferative disease, Hodgkin's disease and inflammatorypseudomotor of the liver.
 33. The method of claim 1, wherein saidcondition is an autoimmune condition chosen from the group of: Gravesdisease, hashimoto's, takayasu's disease, kawasaki's diseases,arteritis, scleroderma, CREST syndrome, allergies, dermatitis,Henoch-schlonlein purpura, goodpasture syndrome, autoimmune thyroiditis,myasthenia gravis, Reiter's disease, raynaud's, and lupus.
 34. Themethod of claim 1, wherein said condition is an inflammatory conditionchosen from the group of: acute respiratory distress syndrome, multiplesclerosis, juvenile rheumatoid arthritis, juvenile chronic arthritis andrheumatoid arthritis.
 35. The method of claim 1, wherein said conditionis an infectious disease chosen from the group: sepsis, viral and fungalinfections, diseases of wound healing, wound healing, tuberculosis,infection, acquired immune deficiency syndrome and humanimmunodeficiency virus.
 36. The method of claim 1, wherein saidcondition is a pulmonary condition chosen from the group of: tachypnea,fibrotic lung diseases such as cystic fibrosis and the like,interstitial lung disease, desquamative interstitial pneumonitis,non-specific interstitial pneumonitis, lymphocytic interstitialpneumonitis, usual interstitial pneumonitis, idiopathic pulmonaryfibrosis, pulmonary edema, aspiration, asphyxiation, pneumothorax,right-to-left shunts, left-to-right shunts and respiratory failure. 37.The method of claim 1, wherein said condition is a transplant-relatedcondition chosen from the group of: transplant rejection,transplant-related tachycardia, transplant related renal failure,transplant related bowel dysmotility and transplant-relatedhyperreninemia.
 38. The method of claim 1, wherein said condition is agastrointestinal condition chosen from the group of: hepatitis,xerostomia, bowel mobility, peptic ulcer disease, constipation, ileus,irritable bowel syndrome, post-operative bowel dysmotility, inflammatorybowel disease and typhilitis.
 39. The method of claim 1, wherein saidcondition is an endocrine condition chosen from the group of:hypothyroidism, hyperglycemia, diabetes, obesity, syndrome X, insulinresistance and polycycstic ovarian syndrome.
 40. The method of claim 1,wherein said condition is a skin condition chosen from the group of:wrinkles, cutaneous vasculitis and psoriasis.
 41. The method of claim 1,wherein said condition is an aging associated condition chosen from thegroup of: shy dragers, multi-system atrophy, age related inflammationconditions, and cancer.
 42. The method of claim 1, wherein saidcondition is a neurologic condition chosen from the group of: epilepsy,seizures, stroke, insomnia, cerebral vascular accident, transientischemic attacks, stress, bipolar disorder, concussions, post-concussivesyndrome, cerebral vascular vasospasm, depression, schizophrenia,central sleep apnea and obstructive sleep apnea.
 43. The method of claim1, wherein said condition is aTh-2 dominant condition chosen from thegroup of: typhilitis, osteoporosis, lymphoma, myasthenia gravis andlupus.
 44. The method of claim 1, wherein said condition is a conditionthat causes at least one of: hypoxia, hypercarbia, hypercapnia, acidosisand acidemia.
 45. The method of claim 44, wherein said conditions ischosen from the group of: acute pulmonary embolism, sudden infant deathsyndrome, sudden adult death syndrome, chronic pulmonary embolism,pleural effusion, cardiogenic pulmonary edema, non-cardiogenic pulmonaryedema, acute respiratory distress syndrome, neurogenic edema,hypercapnia, academia, renal tubular acidosis and lung diseases thatcause acidosis.
 46. The method of claim 1, wherein said condition is apediatric-related condition chosen from the group of: respiratorydistress syndrome, sudden infant death syndrome, hirschsprung disease,bronchopulmonary dysplasia, congenital megacolon and aganglionosis. 47.The method of claim 1, wherein said condition is an OB-GYN conditionchosen from the group of: amniotic fluid embolism, pregnancy-relatedarrhythmias, fetal stress syndrome, fetal hypoxia, menopausal mooddisorders, premenstrual mood disorders, and amniotic fluid embolism. 48.The method of claim 1, wherein said condition is a sudden death syndromechosen from the group of: sudden infant death syndrome and sudden adultdeath syndrome.
 49. The method of claim 1, wherein said condition isfibrosis.
 50. The method of claim 1, wherein said condition is apost-operative recovery condition chosen from the group of:post-operative pain, post operative ileus, post-operative fever andpost-operative nausea.
 51. The method of claim 1, wherein said conditionis a post-procedural recovery condition chosen from the group of:post-procedural pain, post procedural ileus, post-procedural fever andpost-procedural nausea.
 52. The method of claim 1, wherein saidcondition is chronic pain.
 53. The method of claim 1, wherein saidcondition is trauma.
 54. The method of claim 1, wherein said conditionis a disorder of thermoregulation.
 55. The method of claim 1, whereinsaid condition is cyclic vomiting syndrome.
 56. An algorithm foradministering said at least one beta-blocker to said subject inaccordance with method of claim 1 recorded on a computer-readablemedium.
 57. A system comprising: (a) an algorithm for administering saidat least one beta-blocker to said subject in accordance with method ofclaim 1 recorded on a computer-readable medium (b) a pharmaceuticallyeffective amount of at least one beta-blocker, and (c) a drug deliverydevice.
 58. The system of claim 57, wherein said at least onebeta-blocker is chosen from atenolol, betaxolol, bisoprolol, carvedilol,esmolol, labetalol, metoprolol, nadolol, pindolol, propranolol, sotalol,timolol, acebutalol, oxprenolol, carvedilol, and entbutolol.
 59. Thesystem of claim 57, wherein said drug delivery device is an implantabledrug delivery device.
 60. The system of claim 57, further comprising apharmaceutically acceptable amount of at least one non-beta-blockeragent.
 61. A kit comprising: (a) a pharmaceutically effective amount ofat least one beta-blocker; and (b) instructions for practicing themethod of claim 1.